rs9478320

Variant names:

• chr6-152350340-A-C
• rs9478320
• NM_182961.4:c.11734-5T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-152350340-A-C
• chr6-152350340-A-G
• chr6-152350340-A-T

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.11734-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,613,580 control chromosomes in the GnomAD database, including 294,813 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26719 hom., cov: 31)
  • Exomes 𝑓: 0.60 (268094 hom.)
• Consequence: SYNE1 NM_182961.4 splice_region, intron
• Scores: Splicing: ADA: 0.7992
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.420
• Publications: 16 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=-0.82).
• BP6: Variant 6-152350340-A-C is Benign according to our data. Variant chr6-152350340-A-C is described in ClinVar as Benign. ClinVar VariationId is 263075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.11734-5T>G		splice_region_variant, intron_variant	Intron 71 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.11734-5T>G		splice_region_variant, intron_variant	Intron 71 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.11688+278T>G		intron_variant	Intron 71 of 145	1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.4872-5T>G		splice_region_variant, intron_variant	Intron 14 of 18	1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89913 AN: 151844 Hom.: 26695 Cov.: 31

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.600

GnomAD2 exomes AF: 0.589 AC: 147870 AN: 250998 AF XY: 0.586

Gnomad AFR exome AF: 0.566

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.606

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.605 AC: 883707 AN: 1461618 Hom.: 268094 Cov.: 55 AF XY: 0.602 AC XY: 437612 AN XY: 727096

African (AFR) AF: 0.560 AC: 18756 AN: 33472

American (AMR) AF: 0.606 AC: 27125 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16934 AN: 26136

East Asian (EAS) AF: 0.640 AC: 25391 AN: 39700

South Asian (SAS) AF: 0.524 AC: 45220 AN: 86254

European-Finnish (FIN) AF: 0.546 AC: 29144 AN: 53372

Middle Eastern (MID) AF: 0.514 AC: 2965 AN: 5768

European-Non Finnish (NFE) AF: 0.613 AC: 682004 AN: 1111802

Other (OTH) AF: 0.599 AC: 36168 AN: 60390

GnomAD4 genome AF: 0.592 AC: 89986 AN: 151962 Hom.: 26719 Cov.: 31 AF XY: 0.587 AC XY: 43624 AN XY: 74272

African (AFR) AF: 0.570 AC: 23634 AN: 41432

American (AMR) AF: 0.617 AC: 9412 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2225 AN: 3470

East Asian (EAS) AF: 0.622 AC: 3207 AN: 5156

South Asian (SAS) AF: 0.534 AC: 2574 AN: 4820

European-Finnish (FIN) AF: 0.534 AC: 5635 AN: 10560

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41373 AN: 67958

Other (OTH) AF: 0.603 AC: 1268 AN: 2104

Alfa AF: 0.604 Hom.: 75231

Bravo AF: 0.598

Asia WGS AF: 0.598 AC: 2081 AN: 3478

EpiCase AF: 0.597

EpiControl AF: 0.594

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 02, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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	-0.82
CADD	Benign	9.3
DANN	Benign	0.47
PhyloP100		0.42
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.18

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

Other links and lift over

dbSNP: rs9478320; hg19: chr6-152671475; COSMIC: COSV54935109;