rs4331993

Variant names:

• chr6-152472437-T-A
• rs4331993
• NM_182961.4:c.1351-24A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152472437-T-A
• chr6-152472437-T-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.1351-24A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,557,906 control chromosomes in the GnomAD database, including 65,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11878 hom., cov: 30)
  • Exomes 𝑓: 0.33 (53665 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.63
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=-0.77).
• BP6: Variant 6-152472437-T-A is Benign according to our data. Variant chr6-152472437-T-A is described in ClinVar as Benign. ClinVar VariationId is 262162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.1351-24A>T		intron	N/A	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.1372-24A>T		intron	N/A	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.1351-24A>T		intron	N/A	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.1372-24A>T		intron	N/A	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000466159.6	TSL:1	c.1351-24A>T		intron	N/A	ENSP00000446021.1	F5H4Q0

Frequencies

GnomAD3 genomes AF: 0.390 AC: 58761 AN: 150828 Hom.: 11871 Cov.: 30

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.402

GnomAD2 exomes AF: 0.338 AC: 80749 AN: 238760 AF XY: 0.340

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.612

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.330 AC: 464463 AN: 1406962 Hom.: 53665 Cov.: 27 AF XY: 0.333 AC XY: 233500 AN XY: 701478

African (AFR) AF: 0.388 AC: 12299 AN: 31714

American (AMR) AF: 0.258 AC: 11193 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8458 AN: 25394

East Asian (EAS) AF: 0.632 AC: 23459 AN: 37132

South Asian (SAS) AF: 0.408 AC: 33695 AN: 82668

European-Finnish (FIN) AF: 0.311 AC: 16268 AN: 52338

Middle Eastern (MID) AF: 0.405 AC: 2264 AN: 5594

European-Non Finnish (NFE) AF: 0.314 AC: 336518 AN: 1070454

Other (OTH) AF: 0.349 AC: 20309 AN: 58238

GnomAD4 genome AF: 0.390 AC: 58807 AN: 150944 Hom.: 11878 Cov.: 30 AF XY: 0.392 AC XY: 28843 AN XY: 73670

African (AFR) AF: 0.441 AC: 18165 AN: 41158

American (AMR) AF: 0.334 AC: 5067 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1344 AN: 3454

East Asian (EAS) AF: 0.751 AC: 3813 AN: 5074

South Asian (SAS) AF: 0.494 AC: 2362 AN: 4786

European-Finnish (FIN) AF: 0.324 AC: 3355 AN: 10352

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23489 AN: 67662

Other (OTH) AF: 0.401 AC: 837 AN: 2086

Alfa AF: 0.123 Hom.: 403

Bravo AF: 0.394

Asia WGS AF: 0.557 AC: 1940 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.012
DANN	Benign	0.66
PhyloP100		-2.6
PromoterAI		0.036	Neutral
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: rs4331993; hg19: chr6-152793572; COSMIC: COSV55022941; COSMIC: COSV55022941;