19-36006471-A-G

Position:

chr19-36006471-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001039876.3(SYNE4):c.819T>C(p.Cys273=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,612,718 control chromosomes in the GnomAD database, including 1,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 146 hom., cov: 32)

Exomes 𝑓: 0.030 ( 1415 hom. )

Consequence

SYNE4
NM_001039876.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.257

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 19-36006471-A-G is Benign according to our data. Variant chr19-36006471-A-G is described in ClinVar as [Benign]. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.257 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3 linkuse as main transcript	c.819T>C	p.Cys273=	synonymous_variant	5/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9 linkuse as main transcript	c.819T>C	p.Cys273=	synonymous_variant	5/8	5	NM_001039876.3	P2	Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4474

AN:

152038

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.205

Gnomad SAS

AF:

0.0361

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0389

AC:

9596

AN:

246422

Hom.:

428

AF XY:

0.0371

AC XY:

4973

AN XY:

133964

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.202

Gnomad SAS exome

AF:

0.0297

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

AF:

0.0301

AC:

44026

AN:

1460562

Hom.:

1415

Cov.:

AF XY:

0.0301

AC XY:

21866

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.0150

Gnomad4 AMR exome

AF:

0.0344

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.214

Gnomad4 SAS exome

AF:

0.0317

Gnomad4 FIN exome

AF:

0.0317

Gnomad4 NFE exome

AF:

0.0239

Gnomad4 OTH exome

AF:

0.0329

GnomAD4 genome

AF:

0.0294

AC:

4476

AN:

152156

Hom.:

146

Cov.:

AF XY:

0.0312

AC XY:

2317

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0157

Gnomad4 AMR

AF:

0.0264

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.205

Gnomad4 SAS

AF:

0.0357

Gnomad4 FIN

AF:

0.0339

Gnomad4 NFE

AF:

0.0247

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0301

Asia WGS

AF:

0.0830

AC:

288

AN:

3478

EpiCase

AF:

0.0227

EpiControl

AF:

0.0225

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Cys273Cys in exon 5 of SYNE4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.6% (211/8228) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2285423). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.9

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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