6-152488392-A-T

Position:

• chr6-152488392-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.1047+4T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,521,684 control chromosomes in the GnomAD database, including 155,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20762 hom., cov: 32)
  • Exomes 𝑓: 0.43 (134757 hom.)
• Consequence: SYNE1 NM_182961.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002923
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.767

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=-0.67).
• BP6: Variant 6-152488392-A-T is Benign according to our data. Variant chr6-152488392-A-T is described in ClinVar as [Benign]. Clinvar id is 130392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152488392-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.1047+4T>A		splice_donor_region_variant, intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.1047+4T>A		splice_donor_region_variant, intron_variant		1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76822 AN: 151878 Hom.: 20739 Cov.: 32

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.510

GnomAD3 exomes AF: 0.466 AC: 115282 AN: 247410 Hom.: 28758 AF XY: 0.469 AC XY: 62715 AN XY: 133828

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.763

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.434 AC: 594726 AN: 1369688 Hom.: 134757 Cov.: 21 AF XY: 0.438 AC XY: 300592 AN XY: 686342

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.334

Gnomad4 ASJ exome AF: 0.480

Gnomad4 EAS exome AF: 0.781

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.465

GnomAD4 genome AF: 0.506 AC: 76892 AN: 151996 Hom.: 20762 Cov.: 32 AF XY: 0.506 AC XY: 37559 AN XY: 74274

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.509

Alfa AF: 0.401 Hom.: 3679

Bravo AF: 0.513

Asia WGS AF: 0.627 AC: 2179 AN: 3474

EpiCase AF: 0.433

EpiControl AF: 0.434

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2014	- -

Autosomal recessive ataxia, Beauce type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 01, 2018

- -

Arthrogryposis multiplex congenita 3, myogenic type 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	-0.67
CADD	Benign	15
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.028

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

Publications

LitVar

Other links and lift over

dbSNP: rs9397106; hg19: chr6-152809527;