rs2285424

Variant names:

Variant summary

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

The NM_001039876.3(SYNE4):c.225G>A(p.Pro75Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,605,578 control chromosomes in the GnomAD database, including 39,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8857 hom., cov: 31)

Exomes 𝑓: 0.19 ( 30840 hom. )

Consequence

SYNE4
NM_001039876.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.302

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=-0.79).

BP6

Variant 19-36008271-C-T is Benign according to our data. Variant chr19-36008271-C-T is described in ClinVar as [Benign]. Clinvar id is 227084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.302 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3 link	c.225G>A	p.Pro75Pro	synonymous_variant	Exon 2 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.225G>A	p.Pro75Pro	synonymous_variant	Exon 2 of 8	5	NM_001039876.3	ENSP00000316130.3		Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44863

AN:

151876

Hom.:

8819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.0928

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.228

AC:

54961

AN:

240750

Hom.:

8013

AF XY:

0.212

AC XY:

27633

AN XY:

130522

show subpopulations

Gnomad AFR exome

AF:

0.559

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.0974

Gnomad EAS exome

AF:

0.221

Gnomad SAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.191

AC:

278208

AN:

1453586

Hom.:

30840

Cov.:

AF XY:

0.189

AC XY:

136304

AN XY:

722614

show subpopulations

Gnomad4 AFR exome

AF:

0.569

Gnomad4 AMR exome

AF:

0.397

Gnomad4 ASJ exome

AF:

0.0907

Gnomad4 EAS exome

AF:

0.229

Gnomad4 SAS exome

AF:

0.172

Gnomad4 FIN exome

AF:

0.208

Gnomad4 NFE exome

AF:

0.173

Gnomad4 OTH exome

AF:

0.199

GnomAD4 genome

AF:

0.296

AC:

44957

AN:

151992

Hom.:

8857

Cov.:

AF XY:

0.298

AC XY:

22130

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.556

Gnomad4 AMR

AF:

0.336

Gnomad4 ASJ

AF:

0.0928

Gnomad4 EAS

AF:

0.230

Gnomad4 SAS

AF:

0.164

Gnomad4 FIN

AF:

0.220

Gnomad4 NFE

AF:

0.167

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.196

Hom.:

4723

Bravo

AF:

0.318

Asia WGS

AF:

0.217

AC:

755

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro75Pro in exon 2 of SYNE4: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 47.5% (1845/3886) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2285424). -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

Autosomal recessive nonsyndromic hearing loss 76

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.2

DANN

Benign

0.54

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