rs2285424
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001039876.3(SYNE4):c.225G>A(p.Pro75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,605,578 control chromosomes in the GnomAD database, including 39,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.30 ( 8857 hom., cov: 31)
Exomes 𝑓: 0.19 ( 30840 hom. )
Consequence
SYNE4
NM_001039876.3 synonymous
NM_001039876.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.302
Genes affected
SYNE4 (HGNC:26703): (spectrin repeat containing nuclear envelope family member 4) This gene is a member of the nesprin family of genes, that encode KASH (Klarsicht, Anc-1, Syne Homology) domain-containing proteins. In addition to the KASH domain, this protein also contains a coiled-coil and leucine zipper region, a spectrin repeat, and a kinesin-1 binding region. This protein localizes to the outer nuclear membrane, and is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. LINC complexes are formed by SUN (Sad1, UNC-84)-KASH pairs, and are thought to mechanically couple nuclear components to the cytoskeleton. Mutations in this gene have been associated with progressive high-frequency hearing loss. The absence of this protein in mice also caused hearing loss, and changes in hair cell morphology in the ears. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 19-36008271-C-T is Benign according to our data. Variant chr19-36008271-C-T is described in ClinVar as [Benign]. Clinvar id is 227084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.302 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE4 | NM_001039876.3 | c.225G>A | p.Pro75= | synonymous_variant | 2/8 | ENST00000324444.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE4 | ENST00000324444.9 | c.225G>A | p.Pro75= | synonymous_variant | 2/8 | 5 | NM_001039876.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.295 AC: 44863AN: 151876Hom.: 8819 Cov.: 31
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GnomAD3 exomes AF: 0.228 AC: 54961AN: 240750Hom.: 8013 AF XY: 0.212 AC XY: 27633AN XY: 130522
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GnomAD4 exome AF: 0.191 AC: 278208AN: 1453586Hom.: 30840 Cov.: 32 AF XY: 0.189 AC XY: 136304AN XY: 722614
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GnomAD4 genome ? AF: 0.296 AC: 44957AN: 151992Hom.: 8857 Cov.: 31 AF XY: 0.298 AC XY: 22130AN XY: 74278
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | Pro75Pro in exon 2 of SYNE4: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 47.5% (1845/3886) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2285424). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Autosomal recessive nonsyndromic hearing loss 76 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at