rs119103247

chr6-152141290-C-Achr6-152141290-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_182961.4(SYNE1):c.25159G>T(p.Val8387Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8387M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.88

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SYNE1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.25159G>T	p.Val8387Leu	missense_variant	139/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.1693G>T	p.Val565Leu	missense_variant	11/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.25159G>T	p.Val8387Leu	missense_variant	139/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.1693G>T	p.Val565Leu	missense_variant	11/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SYNE1 function (PMID: 17761684). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 2333). This variant is also known as p.V572L, p.V8387L. This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 17761684). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 8339 of the SYNE1 protein (p.Val8339Leu). -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;T;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;D;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;.;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.17	T;.;T;T;T;T;T
Sift4G	Uncertain	0.014	D;D;T;T;D;T;T
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.78
MutPred		0.43		Loss of ubiquitination at K8388 (P = 0.1601);.;.;.;.;.;.;
MVP		0.68
MPC		0.15
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs119103247; hg19: chr6-152462425; COSMIC: COSV99553542;