Submissions for variant NM_022367.4(SEMA4A):c.1000del (p.Arg334fs)

dbSNP: rs756475595

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484646	SCV000566562	likely pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing	The c.1000delA variant in the SEMA4A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1000delA deletion causes a frameshift starting with codon Arginine 334, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Arg334GlyfsX24. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1000delA variant is observed in 8/246268 (0.003%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). We interpret c.1000delA as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484646	SCV004635190	uncertain significance	not provided	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg334Glyfs*24) in the SEMA4A gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SEMA4A cause disease. This variant is present in population databases (rs756475595, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SEMA4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 419032). 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.