rs750797779
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001039876.3(SYNE4):c.559C>T(p.Arg187*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,609,464 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 Likely pathogenic (★★). 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE4 | NM_001039876.3 | c.559C>T | p.Arg187* | stop_gained | 4/8 | ENST00000324444.9 | NP_001034965.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE4 | ENST00000324444.9 | c.559C>T | p.Arg187* | stop_gained | 4/8 | 5 | NM_001039876.3 | ENSP00000316130.3 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151984Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000340 AC: 8AN: 235370Hom.: 0 AF XY: 0.0000390 AC XY: 5AN XY: 128256
GnomAD4 exome AF: 0.0000316 AC: 46AN: 1457480Hom.: 0 Cov.: 35 AF XY: 0.0000304 AC XY: 22AN XY: 724656
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74238
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2023 | This sequence change creates a premature translational stop signal (p.Arg187*) 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 (rs750797779, gnomAD 0.01%). 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: 228293). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2021 | Observed in the heterozygous state in a family with autosomal dominant hearing loss who had a disease-causing variant in the TBC1D24 gene (Parzefall et al., 2020); 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; This variant is associated with the following publications: (PMID: 33281559) - |
Autosomal recessive nonsyndromic hearing loss 76 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 04, 2024 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2015 | The p.Arg187X variant in SYNE4 has not been previously reported in individuals w ith hearing loss, but has been identified in 1/3426 of Finnish chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. This nonsense variant lea ds to a premature termination codon at position 187, which is predicted to lead to a truncated or absent protein. Loss of function of the SYNE4 gene has been as sociated with autosomal recessive hearing loss, based on a report describing two probands with hearing loss who had a homozygous frameshift variant in SYNE4, wh ich segregated in 4 affected family members, and a knock-out mouse model that al so displayed hearing loss (Horn 2013). In summary, although additional studies a re required to fully establish the association between loss of function variants in SYNE4 and autosomal recessive sensorineural hearing loss, based on the avail able data the p.Arg187X variant is likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at