rs186898202

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_001039876.3(SYNE4):c.1020G>A(p.Glu340Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000858 in 1,613,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

SYNE4
NM_001039876.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.206

Publications

1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011614025).

BP6

Variant 19-36003624-C-T is Benign according to our data. Variant chr19-36003624-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 504814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.206 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039876.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	NM_001039876.3	MANE Select	c.1020G>A	p.Glu340Glu	synonymous	Exon 7 of 8	NP_001034965.1	Q8N205-1
	SYNE4	NM_001297735.3		c.681G>A	p.Glu227Glu	synonymous	Exon 5 of 6	NP_001284664.1	Q8N205-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNE4	ENST00000324444.9	TSL:5 MANE Select	c.1020G>A	p.Glu340Glu	synonymous	Exon 7 of 8	ENSP00000316130.3	Q8N205-1
SYNE4	ENST00000340477.9	TSL:1	c.681G>A	p.Glu227Glu	synonymous	Exon 5 of 6	ENSP00000343152.5	Q8N205-2
SYNE4	ENST00000490730.1	TSL:2	c.841G>A	p.Gly281Arg	missense	Exon 7 of 8	ENSP00000422716.1	D6RAE3

Frequencies

GnomAD3 genomes

AF:

0.000789

AC:

120

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000797

AC:

197

AN:

247220

AF XY:

0.000879

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00136

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.000865

AC:

1264

AN:

1460964

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

615

AN XY:

726644

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33472

American (AMR)

AF:

0.00103

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

85886

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000965

AC:

1073

AN:

1111704

Other (OTH)

AF:

0.00113

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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:

0.000788

AC:

120

AN:

152288

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41548

American (AMR)

AF:

0.00235

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000810

Hom.:

Bravo

AF:

0.000918

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000752

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000744

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

SYNE4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Benign

2.5

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.14

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.32

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.76

PhyloP100

0.21

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Polyphen

1.0

MutPred

0.29

Loss of catalytic residue at G281 (P = 0.0429)

MVP

0.57

ClinPred

0.088

GERP RS

1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over