rs4870093

Variant names:

• chr6-152331049-C-T
• rs4870093
• NM_182961.4:c.13636G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.13636G>A​(p.Val4546Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,156 control chromosomes in the GnomAD database, including 39 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.54
• Publications: 7 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 (MetaRNN=0.0048621).
• BP6: Variant 6-152331049-C-T is Benign according to our data. Variant chr6-152331049-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00134 (1960/1461876) while in subpopulation AMR AF = 0.0263 (1178/44724). AF 95% confidence interval is 0.0251. There are 37 homozygotes in GnomAdExome4. There are 914 alleles in the male GnomAdExome4 subpopulation. Median coverage is 83. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.13636G>A	p.Val4546Ile	missense	Exon 78 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.13423G>A	p.Val4475Ile	missense	Exon 77 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.13636G>A	p.Val4546Ile	missense	Exon 78 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.13423G>A	p.Val4475Ile	missense	Exon 77 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000490135.6	TSL:1	n.982G>A		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00440 AC: 1106 AN: 251408 AF XY: 0.00365

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00647

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00134 AC: 1960 AN: 1461876 Hom.: 37 Cov.: 83 AF XY: 0.00126 AC XY: 914 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0263 AC: 1178 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0174 AC: 689 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112012

Other (OTH) AF: 0.00106 AC: 64 AN: 60396

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74460

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.00869 AC: 133 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.0175 Hom.: 2396

Bravo AF: 0.00270

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.055
Sift	Benign	0.25	T
Sift4G	Benign	0.38	T
Polyphen		0.0060	B
Vest4		0.16
MVP		0.31
MPC		0.11
ClinPred		0.016	T
GERP RS		5.2
Varity_R		0.068
gMVP		0.084
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4870093; hg19: chr6-152652184;