rs2285422

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001039876.3(SYNE4):c.834G>C(p.Gln278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,612,406 control chromosomes in the GnomAD database, including 713,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68878 hom., cov: 31)

Exomes 𝑓: 0.94 ( 644717 hom. )

Consequence

SYNE4
NM_001039876.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.167

Publications

31 publications found

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 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

SYNE4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.1539436E-7).

BP6

Variant 19-36006456-C-G is Benign according to our data. Variant chr19-36006456-C-G is described in ClinVar as [Benign]. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3 link	c.834G>C	p.Gln278His	missense_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 link	c.834G>C	p.Gln278His	missense_variant	Exon 5 of 8	5	NM_001039876.3	ENSP00000316130.3		Q8N205-1

Frequencies

GnomAD3 genomes

AF:

0.950

AC:

144518

AN:

152078

Hom.:

68818

Cov.:

show subpopulations

Gnomad AFR

AF:

0.987

Gnomad AMI

AF:

0.911

Gnomad AMR

AF:

0.953

Gnomad ASJ

AF:

0.904

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.843

Gnomad FIN

AF:

0.951

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.949

Gnomad OTH

AF:

0.954

GnomAD2 exomes

AF:

0.927

AC:

228734

AN:

246814

AF XY:

0.924

show subpopulations

Gnomad AFR exome

AF:

0.990

Gnomad AMR exome

AF:

0.947

Gnomad ASJ exome

AF:

0.906

Gnomad EAS exome

AF:

0.794

Gnomad FIN exome

AF:

0.953

Gnomad NFE exome

AF:

0.948

Gnomad OTH exome

AF:

0.940

GnomAD4 exome

AF:

0.939

AC:

1371128

AN:

1460210

Hom.:

644717

Cov.:

AF XY:

0.937

AC XY:

680221

AN XY:

726308

show subpopulations

African (AFR)

AF:

0.991

AC:

33166

AN:

33452

American (AMR)

AF:

0.949

AC:

42305

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.905

AC:

23580

AN:

26066

East Asian (EAS)

AF:

0.808

AC:

32046

AN:

39674

South Asian (SAS)

AF:

0.862

AC:

74134

AN:

86014

European-Finnish (FIN)

AF:

0.954

AC:

50862

AN:

53316

Middle Eastern (MID)

AF:

0.953

AC:

5024

AN:

5270

European-Non Finnish (NFE)

AF:

0.948

AC:

1053653

AN:

1111550

Other (OTH)

AF:

0.935

AC:

56358

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

5187

10374

15560

20747

25934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21586

43172

64758

86344

107930

<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:

0.950

AC:

144638

AN:

152196

Hom.:

68878

Cov.:

AF XY:

0.948

AC XY:

70536

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.987

AC:

40998

AN:

41540

American (AMR)

AF:

0.953

AC:

14580

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.904

AC:

3139

AN:

3472

East Asian (EAS)

AF:

0.805

AC:

4143

AN:

5144

South Asian (SAS)

AF:

0.843

AC:

4065

AN:

4824

European-Finnish (FIN)

AF:

0.951

AC:

10099

AN:

10616

Middle Eastern (MID)

AF:

0.963

AC:

283

AN:

294

European-Non Finnish (NFE)

AF:

0.949

AC:

64489

AN:

67982

Other (OTH)

AF:

0.954

AC:

2013

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

355

709

1064

1418

1773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.945

Hom.:

22031

Bravo

AF:

0.953

TwinsUK

AF:

0.948

AC:

3517

ALSPAC

AF:

0.948

AC:

3654

ESP6500AA

AF:

0.991

AC:

3824

ESP6500EA

AF:

0.951

AC:

7830

ExAC

AF:

0.927

AC:

111943

Asia WGS

AF:

0.848

AC:

2950

AN:

3478

EpiCase

AF:

0.949

EpiControl

AF:

0.951

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gln278His in exon 5 of SYNE4: This variant is not expected to have clinical sign ificance because it has been identified in 4.9% (402/8232) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2285422). -

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

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.73

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0029

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.19

.;T;T

MetaRNN

Benign

6.2e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.6

N;N;.

PhyloP100

-0.17

PrimateAI

Benign

0.35

PROVEAN

Benign

1.6

N;.;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;.;T

Polyphen

0.0

B;B;B

Vest4

0.034

MutPred

0.080

Gain of catalytic residue at Q278 (P = 0.0267);Gain of catalytic residue at Q278 (P = 0.0267);.;

MPC

0.085

ClinPred

0.00036

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over