NM_182961.4:c.1047+4T>A

Variant names:

• chr6-152488392-A-T
• rs9397106
• NM_182961.4:c.1047+4T>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.1047+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,521,684 control chromosomes in the GnomAD database, including 155,519 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00002923
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.767
• Publications: 14 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=-0.67).
• BP6: Variant 6-152488392-A-T is Benign according to our data. Variant chr6-152488392-A-T is described in ClinVar as Benign. ClinVar VariationId is 130392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 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.1047+4T>A		splice_region intron	N/A	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.1068+4T>A		splice_region 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.1047+4T>A		splice_region intron	N/A	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.1068+4T>A		splice_region intron	N/A	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000466159.6	TSL:1	c.1047+4T>A		splice_region intron	N/A	ENSP00000446021.1	F5H4Q0

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

GnomAD2 exomes AF: 0.466 AC: 115282 AN: 247410 AF XY: 0.469

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 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

African (AFR) AF: 0.679 AC: 21408 AN: 31520

American (AMR) AF: 0.334 AC: 14774 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12251 AN: 25498

East Asian (EAS) AF: 0.781 AC: 30540 AN: 39082

South Asian (SAS) AF: 0.522 AC: 43756 AN: 83798

European-Finnish (FIN) AF: 0.408 AC: 20972 AN: 51448

Middle Eastern (MID) AF: 0.522 AC: 2919 AN: 5592

European-Non Finnish (NFE) AF: 0.409 AC: 421435 AN: 1031132

Other (OTH) AF: 0.465 AC: 26671 AN: 57372

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

African (AFR) AF: 0.675 AC: 27969 AN: 41464

American (AMR) AF: 0.418 AC: 6376 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1701 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3921 AN: 5164

South Asian (SAS) AF: 0.541 AC: 2602 AN: 4808

European-Finnish (FIN) AF: 0.400 AC: 4211 AN: 10538

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28632 AN: 67970

Other (OTH) AF: 0.509 AC: 1073 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		0.77
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9397106; hg19: chr6-152809527;