NM_182961.4:c.20571A>T

Variant names:

• chr6-152233922-T-A
• rs34905593
• NM_182961.4:c.20571A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.20571A>T​(p.Ser6857Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,614,078 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.658
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-152233922-T-A is Benign according to our data. Variant chr6-152233922-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2598/152274) while in subpopulation NFE AF = 0.025 (1702/68012). AF 95% confidence interval is 0.024. There are 35 homozygotes in GnomAd4. There are 1314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR gene

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.20571A>T	p.Ser6857Ser	synonymous	Exon 112 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.20358A>T	p.Ser6786Ser	synonymous	Exon 111 of 146	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.20571A>T	p.Ser6857Ser	synonymous	Exon 112 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.20358A>T	p.Ser6786Ser	synonymous	Exon 111 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367256.9	TSL:1	n.4263A>T		non_coding_transcript_exon	Exon 27 of 61

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2599 AN: 152156 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0196 AC: 4935 AN: 251310 AF XY: 0.0211

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0223 AC: 32628 AN: 1461804 Hom.: 426 Cov.: 31 AF XY: 0.0225 AC XY: 16375 AN XY: 727210

African (AFR) AF: 0.00367 AC: 123 AN: 33480

American (AMR) AF: 0.00843 AC: 377 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 449 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.0257 AC: 2220 AN: 86254

European-Finnish (FIN) AF: 0.0341 AC: 1821 AN: 53408

Middle Eastern (MID) AF: 0.0295 AC: 170 AN: 5768

European-Non Finnish (NFE) AF: 0.0236 AC: 26274 AN: 1111950

Other (OTH) AF: 0.0197 AC: 1190 AN: 60392

GnomAD4 genome AF: 0.0171 AC: 2598 AN: 152274 Hom.: 35 Cov.: 32 AF XY: 0.0176 AC XY: 1314 AN XY: 74466

African (AFR) AF: 0.00402 AC: 167 AN: 41562

American (AMR) AF: 0.0127 AC: 195 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4822

European-Finnish (FIN) AF: 0.0300 AC: 318 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1702 AN: 68012

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0217 Hom.: 11

Bravo AF: 0.0143

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	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	-0.54
CADD	Benign	0.12
DANN	Benign	0.66
PhyloP100		-0.66
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: rs34905593; hg19: chr6-152555057;