rs1873176

Variant names:

• chr6-152369424-G-A
• rs1873176
• ENST00000471834.1:n.904C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000471834.1(SYNE1):​n.904C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,612,906 control chromosomes in the GnomAD database, including 225,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16787 hom., cov: 31)
  • Exomes 𝑓: 0.53 (208292 hom.)
• Consequence: SYNE1 ENST00000471834.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.293
• Publications: 7 publications found

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]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-152369424-G-A is Benign according to our data. Variant chr6-152369424-G-A is described in ClinVar as Benign. ClinVar VariationId is 262204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.9651+47C>T		intron_variant	Intron 60 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.9651+47C>T		intron_variant	Intron 60 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69323 AN: 151780 Hom.: 16784 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.489 AC: 122392 AN: 250388 AF XY: 0.491

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.530 AC: 774860 AN: 1461008 Hom.: 208292 Cov.: 37 AF XY: 0.528 AC XY: 383418 AN XY: 726824

African (AFR) AF: 0.272 AC: 9096 AN: 33472

American (AMR) AF: 0.489 AC: 21845 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 14386 AN: 26132

East Asian (EAS) AF: 0.462 AC: 18344 AN: 39692

South Asian (SAS) AF: 0.423 AC: 36476 AN: 86218

European-Finnish (FIN) AF: 0.490 AC: 26120 AN: 53314

Middle Eastern (MID) AF: 0.400 AC: 2245 AN: 5616

European-Non Finnish (NFE) AF: 0.554 AC: 615627 AN: 1111504

Other (OTH) AF: 0.509 AC: 30721 AN: 60358

GnomAD4 genome AF: 0.457 AC: 69343 AN: 151898 Hom.: 16787 Cov.: 31 AF XY: 0.454 AC XY: 33735 AN XY: 74238

African (AFR) AF: 0.287 AC: 11870 AN: 41394

American (AMR) AF: 0.500 AC: 7631 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3470

East Asian (EAS) AF: 0.458 AC: 2349 AN: 5134

South Asian (SAS) AF: 0.435 AC: 2099 AN: 4824

European-Finnish (FIN) AF: 0.480 AC: 5071 AN: 10562

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36842 AN: 67944

Other (OTH) AF: 0.471 AC: 991 AN: 2104

Alfa AF: 0.476 Hom.: 4692

Bravo AF: 0.450

Asia WGS AF: 0.473 AC: 1649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.79
DANN	Benign	0.79
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1873176; hg19: chr6-152690559; COSMIC: COSV55001826;