chr19-36003453-G-GGAGGAGGAA
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001039876.3(SYNE4):c.1090_1098dupTTCCTCCTC(p.Leu366_Leu367insPheLeuLeu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SYNE4
NM_001039876.3 conservative_inframe_insertion
NM_001039876.3 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.351
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SYNE4 | NM_001039876.3 | c.1090_1098dupTTCCTCCTC | p.Leu366_Leu367insPheLeuLeu | conservative_inframe_insertion | Exon 8 of 8 | ENST00000324444.9 | NP_001034965.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152136Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000106 AC: 26AN: 245812Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133576
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1460762Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 726614
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GnomAD4 genome 0.0000394 AC: 6AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74310
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ClinVar
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at