rs768085752

Positions:

• chr6-152331249-C-A
• chr6-152331249-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000367255.10(SYNE1):​c.13436G>T​(p.Arg4479Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. R4479C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNE1 ENST00000367255.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12587115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.13436G>T	p.Arg4479Leu	missense_variant	78/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.13436G>T	p.Arg4479Leu	missense_variant	78/146	1	NM_182961.4	ENSP00000356224	P1
SYNE1	ENST00000423061.6	c.13223G>T	p.Arg4408Leu	missense_variant	77/146	1		ENSP00000396024
SYNE1	ENST00000490135.6	n.782G>T		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461824 Hom.: 0 Cov.: 83 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 4408 of the SYNE1 protein (p.Arg4408Leu). ClinVar contains an entry for this variant (Variation ID: 568434). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.063
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.82	D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.13
Sift	Benign	0.21	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.21	B;.
Vest4		0.19
MutPred		0.47		Loss of disorder (P = 0.1025);.;
MVP		0.42
MPC		0.17
ClinPred		0.44	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs768085752; hg19: chr6-152652384;