rs2285423

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.257

Publications

9 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

new If you want to explore the variant's impact on the transcript NM_001039876.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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 ClinVar as Benign. ClinVar VariationId 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.

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.819T>C	p.Cys273Cys	synonymous	Exon 5 of 8	NP_001034965.1	Q8N205-1
	SYNE4	NM_001297735.3		c.480T>C	p.Cys160Cys	synonymous	Exon 3 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.819T>C	p.Cys273Cys	synonymous	Exon 5 of 8	ENSP00000316130.3	Q8N205-1
SYNE4	ENST00000340477.9	TSL:1	c.480T>C	p.Cys160Cys	synonymous	Exon 3 of 6	ENSP00000343152.5	Q8N205-2
SYNE4	ENST00000872005.1		c.819T>C	p.Cys273Cys	synonymous	Exon 5 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4474

AN:

152038

Hom.:

145

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0301

AC XY:

21866

AN XY:

726534

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2628

5256

7883

10511

13139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1164

2328

3492

4656

5820

<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:

0.0294

AC:

4476

AN:

152156

Hom.:

146

Cov.:

AF XY:

0.0312

AC XY:

2317

AN XY:

74368

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0247

AC:

1680

AN:

67974

Other (OTH)

AF:

0.0275

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

216

432

649

865

1081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0193

Hom.:

Bravo

AF:

0.0301

Asia WGS

AF:

0.0830

AC:

288

AN:

3478

EpiCase

AF:

0.0227

EpiControl

AF:

0.0225

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.9

(source)

DANN

Benign

0.59

PhyloP100

0.26

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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