rs199853331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001039876.3(SYNE4):c.764T>C(p.Ile255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,608,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

SYNE4
NM_001039876.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.12

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009841025).

BP6

Variant 19-36006526-A-G is Benign according to our data. Variant chr19-36006526-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504863.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	NM_001039876.3	MANE Select	c.764T>C	p.Ile255Thr	missense	Exon 5 of 8	NP_001034965.1
	SYNE4	NM_001297735.3		c.425T>C	p.Ile142Thr	missense	Exon 3 of 6	NP_001284664.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE4	ENST00000324444.9	TSL:5 MANE Select	c.764T>C	p.Ile255Thr	missense	Exon 5 of 8	ENSP00000316130.3
SYNE4	ENST00000340477.9	TSL:1	c.425T>C	p.Ile142Thr	missense	Exon 3 of 6	ENSP00000343152.5
SYNE4	ENST00000465425.2	TSL:2	n.876T>C		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000677

AC:

158

AN:

233226

AF XY:

0.000731

show subpopulations

Gnomad AFR exome

AF:

0.000288

Gnomad AMR exome

AF:

0.0000905

Gnomad ASJ exome

AF:

0.00718

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.000525

GnomAD4 exome

AF:

0.000460

AC:

670

AN:

1455986

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

361

AN XY:

723848

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33334

American (AMR)

AF:

0.000137

AC:

AN:

43844

Ashkenazi Jewish (ASJ)

AF:

0.00783

AC:

203

AN:

25926

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39476

South Asian (SAS)

AF:

0.00199

AC:

170

AN:

85276

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52952

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000206

AC:

228

AN:

1109318

Other (OTH)

AF:

0.000749

AC:

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000440

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41524

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000711

Hom.:

Bravo

AF:

0.000385

ESP6500AA

AF:

0.000270

AC:

ESP6500EA

AF:

0.00123

AC:

ExAC

AF:

0.000572

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

SYNE4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Benign

0.018

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.80

M_CAP

Benign

0.0081

MetaRNN

Benign

0.0098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

2.1

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.015

Polyphen

0.42

Vest4

0.30

MVP

0.51

MPC

0.45

ClinPred

0.034

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.11

Mutation Taster

=79/21

polymorphism

(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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over