NM_182961.4:c.13786T>A

Variant names:

• chr6-152330899-A-T
• rs6911096
• NM_182961.4:c.13786T>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.13786T>A​(p.Ser4596Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,614,046 control chromosomes in the GnomAD database, including 473,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49272 hom., cov: 32)
  • Exomes 𝑓: 0.76 (424207 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.49
• Publications: 40 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: Computational evidence support a benign effect (MetaRNN=7.340609E-7).
• BP6: Variant 6-152330899-A-T is Benign according to our data. Variant chr6-152330899-A-T is described in ClinVar as Benign. ClinVar VariationId is 130404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.13786T>A	p.Ser4596Thr	missense	Exon 78 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.13573T>A	p.Ser4525Thr	missense	Exon 77 of 146	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.13786T>A	p.Ser4596Thr	missense	Exon 78 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.13573T>A	p.Ser4525Thr	missense	Exon 77 of 146	ENSP00000396024.1
	SYNE1	ENST00000490135.6	TSL:1	n.1132T>A		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121997 AN: 152102 Hom.: 49213 Cov.: 32

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.766

GnomAD2 exomes AF: 0.780 AC: 195948 AN: 251358 AF XY: 0.766

Gnomad AFR exome AF: 0.891

Gnomad AMR exome AF: 0.867

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.846

Gnomad FIN exome AF: 0.850

Gnomad NFE exome AF: 0.756

Gnomad OTH exome AF: 0.759

GnomAD4 exome AF: 0.760 AC: 1110859 AN: 1461826 Hom.: 424207 Cov.: 65 AF XY: 0.755 AC XY: 549048 AN XY: 727216

African (AFR) AF: 0.888 AC: 29710 AN: 33476

American (AMR) AF: 0.861 AC: 38526 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 18672 AN: 26136

East Asian (EAS) AF: 0.854 AC: 33914 AN: 39700

South Asian (SAS) AF: 0.650 AC: 56044 AN: 86254

European-Finnish (FIN) AF: 0.846 AC: 45163 AN: 53404

Middle Eastern (MID) AF: 0.628 AC: 3620 AN: 5768

European-Non Finnish (NFE) AF: 0.755 AC: 839697 AN: 1111970

Other (OTH) AF: 0.754 AC: 45513 AN: 60394

GnomAD4 genome AF: 0.802 AC: 122114 AN: 152220 Hom.: 49272 Cov.: 32 AF XY: 0.805 AC XY: 59939 AN XY: 74434

African (AFR) AF: 0.889 AC: 36945 AN: 41540

American (AMR) AF: 0.815 AC: 12463 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2425 AN: 3464

East Asian (EAS) AF: 0.847 AC: 4382 AN: 5176

South Asian (SAS) AF: 0.651 AC: 3144 AN: 4826

European-Finnish (FIN) AF: 0.845 AC: 8959 AN: 10600

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.755 AC: 51334 AN: 68014

Other (OTH) AF: 0.769 AC: 1619 AN: 2106

Alfa AF: 0.760 Hom.: 32931

Bravo AF: 0.806

TwinsUK AF: 0.743 AC: 2756

ALSPAC AF: 0.768 AC: 2958

ESP6500AA AF: 0.887 AC: 3910

ESP6500EA AF: 0.749 AC: 6441

ExAC AF: 0.776 AC: 94209

Asia WGS AF: 0.777 AC: 2704 AN: 3478

EpiCase AF: 0.732

EpiControl AF: 0.735

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0010
DANN	Benign	0.20
DEOGEN2	Benign	0.085	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.025	N
PhyloP100		-2.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.049
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.12
ClinPred		0.024	T
GERP RS		-12
Varity_R		0.039
gMVP		0.057
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6911096; hg19: chr6-152652034; COSMIC: COSV54944634; COSMIC: COSV54944634;