Submissions for variant NM_001202.6(BMP4):c.124G>C (p.Ala42Pro)

gnomAD frequency: 0.00026  dbSNP: rs140920120

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001110772	SCV001268250	uncertain significance	Orofacial cleft 11	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001110773	SCV001268251	likely benign	Microphthalmia with brain and digit anomalies	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV001856475	SCV002296377	uncertain significance	Microphthalmia with brain and digit anomalies; Orofacial cleft 11	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 42 of the BMP4 protein (p.Ala42Pro). This variant is present in population databases (rs140920120, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with tooth agenesis (PMID: 23841782). ClinVar contains an entry for this variant (Variation ID: 881629). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects BMP4 function (PMID: 23841782). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002558108	SCV003693044	likely benign	Inborn genetic diseases	2022-01-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV003238838	SCV003936795	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a subtle effect on BMP4 prodomain attachment, storage or transport in the extracellular matrix (Huang et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31128441, 23841782, 29641532, 26740555, 28944238, 35805171)
CeGaT Center for Human Genetics Tuebingen	RCV003238838	SCV004134141	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	BMP4: BP4, BS2