rs186898202

Positions:

chr19-36003624-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_001039876.3(SYNE4):c.1020G>A(p.Glu340=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000858 in 1,613,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

SYNE4
NM_001039876.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.206

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011614025).

BP6

Variant 19-36003624-C-T is Benign according to our data. Variant chr19-36003624-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.206 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE4	NM_001039876.3 linkuse as main transcript	c.1020G>A	p.Glu340=	synonymous_variant	7/8	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9 linkuse as main transcript	c.1020G>A	p.Glu340=	synonymous_variant	7/8	5	NM_001039876.3	ENSP00000316130	P2	Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.000789

AC:

120

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000797

AC:

197

AN:

247220

Hom.:

AF XY:

0.000879

AC XY:

118

AN XY:

134188

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00136

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.000865

AC:

1264

AN:

1460964

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

615

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.000965

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152288

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000921

Hom.:

Bravo

AF:

0.000918

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000752

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000744

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

p.Glu340Glu in exon 7 of SYNE4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (68/57658) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs186898202). -

SYNE4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Benign

2.5

DANN

Benign

0.92

DEOGEN2

Benign

0.14

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.32

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.76

MutationTaster

Benign

1.0

N;N

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Polyphen

1.0

MutPred

0.29

Loss of catalytic residue at G281 (P = 0.0429);

MVP

0.57

ClinPred

0.088

GERP RS

1.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over