rs186898202

chr19-36003624-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001039876.3(SYNE4):c.1020G>A(p.Glu340=) 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.206

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.1020G>A	p.Glu340=	synonymous_variant	7/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.1020G>A	p.Glu340=	synonymous_variant	7/8	5	NM_001039876.3	P2

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152170 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.000797 AC: 197 AN: 247220 Hom.: 0 AF XY: 0.000879 AC XY: 118 AN XY: 134188

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000846 AC XY: 615 AN XY: 726644

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.000965

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152288 Hom.: 1 Cov.: 31 AF XY: 0.000806 AC XY: 60 AN XY: 74470

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000921 Hom.: 0

Bravo AF: 0.000918

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000752 AC: 3

ESP6500EA AF: 0.00108 AC: 9

ExAC AF: 0.000744 AC: 90

EpiCase AF: 0.000872

EpiControl AF: 0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

p.Glu340Glu in exon 7 of SYNE4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (68/57658) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs186898202). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	2.5
Dann	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
MutPred		0.29		Loss of catalytic residue at G281 (P = 0.0429);
MVP		0.57
ClinPred		0.088	T
GERP RS		1.4

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

LitVar

Other links and lift over

dbSNP: rs186898202; hg19: chr19-36494526;