rs200484521
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001039876.3(SYNE4):c.699G>A(p.Trp233*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,607,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001039876.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE4 | NM_001039876.3 | c.699G>A | p.Trp233* | stop_gained | 5/8 | ENST00000324444.9 | NP_001034965.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE4 | ENST00000324444.9 | c.699G>A | p.Trp233* | stop_gained | 5/8 | 5 | NM_001039876.3 | ENSP00000316130.3 |
Frequencies
GnomAD3 genomes AF: 0.000637 AC: 97AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000322 AC: 75AN: 232926Hom.: 0 AF XY: 0.000307 AC XY: 39AN XY: 127042
GnomAD4 exome AF: 0.000803 AC: 1169AN: 1455368Hom.: 0 Cov.: 35 AF XY: 0.000741 AC XY: 536AN XY: 723424
GnomAD4 genome AF: 0.000637 AC: 97AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000552 AC XY: 41AN XY: 74334
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2024 | Observed with a pathogenic variant on the opposite allele (in trans) and with a pathogenic variant (phase unknown) in multiple patients referred for genetic testing at GeneDx; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign in association with hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 23348741, 29245897, 33057194, 35982159) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Trp233*) in the SYNE4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNE4 are known to be pathogenic (PMID: 23348741, 28958982). This variant is present in population databases (rs200484521, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with SYNE4-related conditions. ClinVar contains an entry for this variant (Variation ID: 228294). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 76 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2021 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 04, 2024 | Variant summary: SYNE4 c.699G>A (p.Trp233X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00079 in 1607538 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database (v4). This frequency is not higher than estimated for a pathogenic variant in SYNE4 causing Nonsyndromic Hearing Loss And Deafness, Type 76 (0.001 vs 0.0011), allowing no strong conclusion about variant significance. To our knowledge, no occurrence of c.699G>A in individuals affected with Nonsyndromic Hearing Loss And Deafness and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 228294). Based on the evidence outlined above, the variant was classified as pathogenic. - |
SYNE4-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 18, 2024 | The SYNE4 c.699G>A variant is predicted to result in premature protein termination (p.Trp233*). At PreventionGenetics, this variant has been observed in the homozygous state or heterozygous state along with a likely pathogenic variant in four individuals undergoing testing for hearing loss from three apparently unrelated families (internal data). This variant has also been reported in the heterozygous state in one individual with a developmental disorder, although conclusive evidence of pathogenicity was not presented (Table S1, Kaplanis et al. 2020. PubMed ID: 33057194; Supplementary Data 3, Zhou et al. 2022. PubMed ID: 35982159). This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In relation to autosomal recessive hearing loss, this variant is interpreted as likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 07, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at