rs2285424

Variant names:

• chr19-36008271-C-T
• rs2285424
• NM_001039876.3:c.225G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.302

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]

ACMG classification

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	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	c.225G>A	p.Pro75Pro	synonymous_variant	Exon 2 of 8	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44863 AN: 151876 Hom.: 8819 Cov.: 31

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

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.: 32 AF XY: 0.189 AC XY: 136304 AN XY: 722614

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.: 31 AF XY: 0.298 AC XY: 22130 AN XY: 74278

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

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 76 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs2285424; hg19: chr19-36499173; COSMIC: COSV53324693; COSMIC: COSV53324693;