rs138787817

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001039876.3(SYNE4):c.96C>T(p.Thr32Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,952 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 11 hom. )

Consequence

SYNE4
NM_001039876.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.199

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:

ENSG00000248101 (HGNC:):

ENSG00000248101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.028).

BP6

Variant 19-36008586-G-A is Benign according to our data. Variant chr19-36008586-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.199 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00144 (219/152268) while in subpopulation EAS AF = 0.00656 (34/5184). AF 95% confidence interval is 0.00482. There are 3 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3 link	c.96C>T	p.Thr32Thr	synonymous_variant	Exon 1 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.96C>T	p.Thr32Thr	synonymous_variant	Exon 1 of 8	5	NM_001039876.3	ENSP00000316130.3		Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

220

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00674

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00230

AC:

573

AN:

249074

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00723

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.000470

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.000971

AC:

1420

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000963

AC XY:

700

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44716

Gnomad4 ASJ exome

AF:

0.00145

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00421

AC:

167

AN:

39700

Gnomad4 SAS exome

AF:

0.00126

AC:

109

AN:

86254

Gnomad4 FIN exome

AF:

0.0143

AC:

765

AN:

53400

Gnomad4 NFE exome

AF:

0.000173

AC:

192

AN:

1111904

Gnomad4 Remaining exome

AF:

0.00240

AC:

145

AN:

60374

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152268

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000240651

AN:

0.0000240651

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.000577

AC:

0.000576701

AN:

0.000576701

Gnomad4 EAS

AF:

0.00656

AC:

0.00655864

AN:

0.00655864

Gnomad4 SAS

AF:

0.00166

AC:

0.00166044

AN:

0.00166044

Gnomad4 FIN

AF:

0.0138

AC:

0.0137632

AN:

0.0137632

Gnomad4 NFE

AF:

0.000368

AC:

0.000367561

AN:

0.000367561

Gnomad4 OTH

AF:

0.00142

AC:

0.00141777

AN:

0.00141777

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000525

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr32Thr in exon 1 of SYNE4: This variant is not expected to have clinical sig nificance because it has been identified in 1.3 % (86/6534) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs138787817). -

SYNE4-related disorder

Benign:1

Jun 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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_noAF

Benign

-0.75

CADD

Benign

5.7

DANN

Benign

0.64

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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