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

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

SYNE4
NM_001039876.3 stop_gained

Scores

2
3
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.727
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-36006591-C-T is Pathogenic according to our data. Variant chr19-36006591-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228294.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SYNE4NM_001039876.3 linkuse as main transcriptc.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
SYNE4ENST00000324444.9 linkuse as main transcriptc.699G>A p.Trp233* stop_gained 5/85 NM_001039876.3 ENSP00000316130.3 Q8N205-1

Frequencies

GnomAD3 genomes
AF:
0.000637
AC:
97
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00116
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000322
AC:
75
AN:
232926
Hom.:
0
AF XY:
0.000307
AC XY:
39
AN XY:
127042
show subpopulations
Gnomad AFR exome
AF:
0.000513
Gnomad AMR exome
AF:
0.0000605
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000685
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000585
Gnomad OTH exome
AF:
0.000528
GnomAD4 exome
AF:
0.000803
AC:
1169
AN:
1455368
Hom.:
0
Cov.:
35
AF XY:
0.000741
AC XY:
536
AN XY:
723424
show subpopulations
Gnomad4 AFR exome
AF:
0.000359
Gnomad4 AMR exome
AF:
0.0000457
Gnomad4 ASJ exome
AF:
0.0000386
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000470
Gnomad4 FIN exome
AF:
0.0000190
Gnomad4 NFE exome
AF:
0.00100
Gnomad4 OTH exome
AF:
0.000583
GnomAD4 genome
AF:
0.000637
AC:
97
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.000552
AC XY:
41
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.000314
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00116
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000747
Hom.:
0
Bravo
AF:
0.000620
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00135
AC:
5
ESP6500EA
AF:
0.000733
AC:
6
ExAC
AF:
0.000331
AC:
40

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 06, 2024Observed 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 30, 2021- -
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 04, 2024Variant 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 providedclinical testingPreventionGenetics, part of Exact SciencesSep 18, 2024The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 07, 2020proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
37
DANN
Uncertain
0.99
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.23
N
Vest4
0.18
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200484521; hg19: chr19-36497493; API