rs1554686616

chr6-152430495-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_182961.4(SYNE1):c.4676A>T(p.Glu1559Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3217368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.4676A>T	p.Glu1559Val	missense_variant	35/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.4676A>T	p.Glu1559Val	missense_variant	35/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.4697A>T	p.Glu1566Val	missense_variant	35/146	1
SYNE1	ENST00000461872.6	n.4894A>T		non_coding_transcript_exon_variant	33/55	1
SYNE1	ENST00000367253.8	c.4676A>T	p.Glu1559Val	missense_variant	33/36	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

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

Nov 06, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with SYNE1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with valine at codon 1566 of the SYNE1 protein (p.Glu1566Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Uncertain	0.53	D;.;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;D;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	0.51	N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;.;D;D
REVEL	Benign	0.089
Sift	Uncertain	0.0060	D;.;D;T
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.32	B;.;.;B
Vest4		0.46
MutPred		0.42		Loss of disorder (P = 0.0064);.;.;Loss of disorder (P = 0.0064);
MVP		0.58
MPC		0.44
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.27
gMVP		0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554686616; hg19: chr6-152751630;