NM_001039876.3:c.699G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001039876.3(SYNE4):c.699G>A(p.Trp233*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,607,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

SYNE4
NM_001039876.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 0.727

Publications

3 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 19-36006591-C-T is Pathogenic according to our data. Variant chr19-36006591-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228294.

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.699G>A	p.Trp233*	stop_gained	Exon 5 of 8	NP_001034965.1
	SYNE4	NM_001297735.3		c.360G>A	p.Trp120*	stop_gained	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.699G>A	p.Trp233*	stop_gained	Exon 5 of 8	ENSP00000316130.3
SYNE4	ENST00000340477.9	TSL:1	c.360G>A	p.Trp120*	stop_gained	Exon 3 of 6	ENSP00000343152.5
SYNE4	ENST00000872005.1		c.699G>A	p.Trp233*	stop_gained	Exon 5 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000322

AC:

AN:

232926

AF XY:

0.000307

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.0000605

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000585

Gnomad OTH exome

AF:

0.000528

GnomAD4 exome

AF:

0.000803

AC:

1169

AN:

1455368

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

536

AN XY:

723424

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33384

American (AMR)

AF:

0.0000457

AC:

AN:

43742

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85168

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00100

AC:

1114

AN:

1109102

Other (OTH)

AF:

0.000583

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.000637

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41448

American (AMR)

AF:

0.000262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000747

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00135

AC:

ESP6500EA

AF:

0.000733

AC:

ExAC

AF:

0.000331

AC:

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)

Autosomal recessive nonsyndromic hearing loss 76 (2)

Nonsyndromic genetic hearing loss (1)

not specified (1)

SYNE4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.23

PhyloP100

0.73

Vest4

0.18

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=50/150

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over