rs200484521

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

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

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 0.727

Publications

3 publications found

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]

SYNE4 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 76
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SYNE4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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 VariationId is 228294.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3 link	c.699G>A	p.Trp233*	stop_gained	Exon 5 of 8	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9 link	c.699G>A	p.Trp233*	stop_gained	Exon 5 of 8	5	NM_001039876.3	ENSP00000316130.3		Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

152170

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000322

AC:

AN:

232926

AF XY:

0.000307

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 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.:

Cov.:

AF XY:

0.000741

AC XY:

536

AN XY:

723424

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33384

American (AMR)

AF:

0.0000457

AC:

AN:

43742

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85168

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00100

AC:

1114

AN:

1109102

Other (OTH)

AF:

0.000583

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000637

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41448

American (AMR)

AF:

0.000262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000747

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00135

AC:

ESP6500EA

AF:

0.000733

AC:

ExAC

AF:

0.000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SYNE4: PVS1:Strong, PM2:Supporting -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Jun 02, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed 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) -

Autosomal recessive nonsyndromic hearing loss 76

Pathogenic:2

Nov 30, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Jan 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant 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

Sep 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The 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

Jan 07, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.23

PhyloP100

0.73

Vest4

0.18

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=50/150

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over