rs9478310

Variant names:

• chr6-152282004-T-C
• rs9478310
• NM_182961.4:c.18208-24A>G

Variant summary

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

The NM_182961.4(SYNE1):​c.18208-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,610,520 control chromosomes in the GnomAD database, including 3,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.069 (421 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3574 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 4 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-152282004-T-C is Benign according to our data. Variant chr6-152282004-T-C is described in ClinVar as Benign. ClinVar VariationId is 262174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.18208-24A>G		intron_variant	Intron 96 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.18208-24A>G		intron_variant	Intron 96 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10519 AN: 152128 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0671 AC: 16449 AN: 245092 AF XY: 0.0707

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.0362

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0763

GnomAD4 exome AF: 0.0660 AC: 96315 AN: 1458274 Hom.: 3574 Cov.: 30 AF XY: 0.0683 AC XY: 49578 AN XY: 725612

African (AFR) AF: 0.0868 AC: 2902 AN: 33442

American (AMR) AF: 0.0384 AC: 1719 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2994 AN: 26128

East Asian (EAS) AF: 0.0479 AC: 1901 AN: 39688

South Asian (SAS) AF: 0.119 AC: 10227 AN: 86198

European-Finnish (FIN) AF: 0.0313 AC: 1608 AN: 51400

Middle Eastern (MID) AF: 0.126 AC: 721 AN: 5744

European-Non Finnish (NFE) AF: 0.0626 AC: 69549 AN: 1110630

Other (OTH) AF: 0.0778 AC: 4694 AN: 60322

GnomAD4 genome AF: 0.0692 AC: 10530 AN: 152246 Hom.: 421 Cov.: 32 AF XY: 0.0686 AC XY: 5109 AN XY: 74462

African (AFR) AF: 0.0872 AC: 3622 AN: 41536

American (AMR) AF: 0.0513 AC: 784 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3472

East Asian (EAS) AF: 0.0553 AC: 287 AN: 5190

South Asian (SAS) AF: 0.104 AC: 503 AN: 4822

European-Finnish (FIN) AF: 0.0296 AC: 314 AN: 10612

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0633 AC: 4304 AN: 68014

Other (OTH) AF: 0.0785 AC: 166 AN: 2114

Alfa AF: 0.0757 Hom.: 151

Bravo AF: 0.0720

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 28, 2018

GeneDx

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	-0.90
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-1.5
La Branchor		0.53
BranchPoint Hunter		1.0
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: rs9478310; hg19: chr6-152603139; COSMIC: COSV54939256; COSMIC: COSV54939256;