19-36006471-A-G

Variant names:

• chr19-36006471-A-G
• rs2285423
• NM_001039876.3:c.819T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001039876.3(SYNE4):​c.819T>C​(p.Cys273Cys) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.257
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar as Benign. Clinvar id is 227090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006471-A-G is described in CliVar 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 rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3	c.819T>C	p.Cys273Cys	synonymous_variant	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	c.819T>C	p.Cys273Cys	synonymous_variant	Exon 5 of 8	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4474 AN: 152038 Hom.: 145 Cov.: 32

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

GnomAD2 exomes AF: 0.0389 AC: 9596 AN: 246422 AF XY: 0.0371

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 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.: 35 AF XY: 0.0301 AC XY: 21866 AN XY: 726534

African (AFR) AF: 0.0150 AC: 502 AN: 33452

American (AMR) AF: 0.0344 AC: 1536 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 386 AN: 26100

East Asian (EAS) AF: 0.214 AC: 8504 AN: 39656

South Asian (SAS) AF: 0.0317 AC: 2730 AN: 86074

European-Finnish (FIN) AF: 0.0317 AC: 1689 AN: 53314

Middle Eastern (MID) AF: 0.0253 AC: 140 AN: 5534

European-Non Finnish (NFE) AF: 0.0239 AC: 26556 AN: 1111492

Other (OTH) AF: 0.0329 AC: 1983 AN: 60318

GnomAD4 genome AF: 0.0294 AC: 4476 AN: 152156 Hom.: 146 Cov.: 32 AF XY: 0.0312 AC XY: 2317 AN XY: 74368

African (AFR) AF: 0.0157 AC: 654 AN: 41524

American (AMR) AF: 0.0264 AC: 403 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3464

East Asian (EAS) AF: 0.205 AC: 1056 AN: 5150

South Asian (SAS) AF: 0.0357 AC: 172 AN: 4822

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1680 AN: 67974

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0193 Hom.: 29

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

Submissions by phenotype

not provided Benign:3

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 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

- -

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

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). -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.9
DANN	Benign	0.59
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2285423; hg19: chr19-36497373; COSMIC: COSV53324624; COSMIC: COSV53324624;