rs9478320

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7992
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.420

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 Benign. Variant got -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 id is 263075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152350340-A-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.11734-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.11734-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_182961.4	ENSP00000356224	P1
SYNE1	ENST00000423061.6	c.11688+278T>G		intron_variant		1		ENSP00000396024
SYNE1	ENST00000471834.1	n.4872-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.589 AC: 147870 AN: 250998 Hom.: 43922 AF XY: 0.586 AC XY: 79535 AN XY: 135658

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 SAS exome AF: 0.525

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

Gnomad4 AFR exome AF: 0.560

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.599

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

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.603

Alfa AF: 0.606 Hom.: 46237

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive ataxia, Beauce type Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.3
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

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