rs767844376

chr6-152300684-C-Achr6-152300684-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_182961.4(SYNE1):c.17639G>T(p.Arg5880Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R5880C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.91

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.24212298).
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.17639G>T	p.Arg5880Leu	missense_variant	93/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.17639G>T	p.Arg5880Leu	missense_variant	93/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251416 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2023	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 5809 of the SYNE1 protein (p.Arg5809Leu). This variant is present in population databases (rs767844376, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 281233). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D;.;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;.;D;D
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		0.77	P;.;.;.
Vest4		0.54
MVP		0.58
MPC		0.18
ClinPred		0.20	T
GERP RS		4.8
Varity_R		0.43
gMVP		0.46

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs767844376; hg19: chr6-152621819; COSMIC: COSV54919033;