19-36003427-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS1
The NM_001039876.3(SYNE4):c.1125C>T(p.Pro375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,738 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00023 ( 3 hom. )
Consequence
SYNE4
NM_001039876.3 synonymous
NM_001039876.3 synonymous
Scores
1
1
12
Clinical Significance
Conservation
PhyloP100: 0.538
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 -11 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0047580004).
BP6
?
Variant 19-36003427-G-A is Benign according to our data. Variant chr19-36003427-G-A is described in ClinVar as [Benign]. Clinvar id is 795150.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
Synonymous conserved (PhyloP=0.538 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000234 (342/1461494) while in subpopulation SAS AF= 0.00374 (322/86184). AF 95% confidence interval is 0.0034. There are 3 homozygotes in gnomad4_exome. There are 246 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE4 | NM_001039876.3 | c.1125C>T | p.Pro375= | synonymous_variant | 8/8 | ENST00000324444.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE4 | ENST00000324444.9 | c.1125C>T | p.Pro375= | synonymous_variant | 8/8 | 5 | NM_001039876.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152126Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000425 AC: 105AN: 247174Hom.: 0 AF XY: 0.000611 AC XY: 82AN XY: 134260
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GnomAD4 exome AF: 0.000234 AC: 342AN: 1461494Hom.: 3 Cov.: 31 AF XY: 0.000338 AC XY: 246AN XY: 727008
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GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152244Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16AN XY: 74448
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Polyphen
B
MutPred
Gain of sheet (P = 0.0266);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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