Submissions for variant NM_004606.5(TAF1):c.3648A>G (p.Gln1216=)

dbSNP: rs2034990430

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genome Medicine, Institute for Basic Research in Developmental Disabilities	RCV002274815	SCV002559793	likely pathogenic	Intellectual disability, X-linked, syndromic 33	2022-08-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235696	SCV003933777	uncertain significance	not specified	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: TAF1 c.3648A>G alters a non-conserved nucleotide resulting in a synonymous change predicted to result in an alternate novel cryptic exonic 3' splice acceptor site and a frameshift change (p.Arg1228Ilefs*16). Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic splice 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a 28bp deletion using blood as a specimen type (O'Rawe_2015). These findings are consistent with the computational predictions. However, both the normal and the deleted transcripts were observed in the affected individual. The variant was absent in 182734 control chromosomes. c.3708A>G has been reported in the literature as a maternally inherited variant in an individual affected with Mental Retardation, X-Linked (O'Rawe_2015). However, this variant has also been observed in a presumably unaffected father at our laboratory. The following publication has been ascertained in the context of this evaluation (PMID: 26637982). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560913	SCV004300113	likely pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 26637982). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1700566). This variant has been observed in individual(s) with TAF1-related intellectual disability with facial dysmorphism (PMID: 26637982). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1236 of the TAF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TAF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV003560913	SCV005325822	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26637982)