6-152399844-A-T

Variant names:

• chr6-152399844-A-T
• rs79428643
• NM_182961.4:c.7030-21T>A

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.7030-21T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,607,480 control chromosomes in the GnomAD database, including 1,229 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 0.051 (631 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (598 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520
• Publications: 1 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=-0.82).
• BP6: Variant 6-152399844-A-T is Benign according to our data. Variant chr6-152399844-A-T is described in ClinVar as Benign. ClinVar VariationId is 262199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.7030-21T>A		intron_variant	Intron 47 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.7030-21T>A		intron_variant	Intron 47 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.7051-21T>A		intron_variant	Intron 47 of 145	1		ENSP00000396024.1
SYNE1	ENST00000461872.6	n.7248-21T>A		intron_variant	Intron 45 of 54	1

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7742 AN: 152134 Hom.: 629 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0136 AC: 3407 AN: 250620 AF XY: 0.00983

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.00939

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.00606

GnomAD4 exome AF: 0.00559 AC: 8131 AN: 1455228 Hom.: 598 Cov.: 30 AF XY: 0.00492 AC XY: 3565 AN XY: 724322

African (AFR) AF: 0.180 AC: 6016 AN: 33366

American (AMR) AF: 0.0114 AC: 511 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000652 AC: 17 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86122

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53386

Middle Eastern (MID) AF: 0.00817 AC: 47 AN: 5752

European-Non Finnish (NFE) AF: 0.000664 AC: 734 AN: 1106028

Other (OTH) AF: 0.0128 AC: 771 AN: 60148

GnomAD4 genome AF: 0.0511 AC: 7773 AN: 152252 Hom.: 631 Cov.: 32 AF XY: 0.0499 AC XY: 3713 AN XY: 74450

African (AFR) AF: 0.176 AC: 7293 AN: 41522

American (AMR) AF: 0.0220 AC: 336 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68018

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.00392 Hom.: 7

Bravo AF: 0.0593

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

Jul 31, 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	-0.82
CADD	Benign	0.18
DANN	Benign	0.70
PhyloP100		-0.52
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: rs79428643; hg19: chr6-152720979;