rs369775705

Variant names:

• chr6-152430561-C-T
• rs369775705
• NM_182961.4:c.4610G>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.4610G>A​(p.Arg1537Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000941 in 1,614,078 control chromosomes in the GnomAD database, including 23 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1537G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (22 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.56
• Publications: 3 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=0.0023553371).
• BP6: Variant 6-152430561-C-T is Benign according to our data. Variant chr6-152430561-C-T is described in ClinVar as Benign. ClinVar VariationId is 281160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000657 (100/152248) while in subpopulation SAS AF = 0.0199 (96/4826). AF 95% confidence interval is 0.0167. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 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.4610G>A	p.Arg1537Gln	missense	Exon 35 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.4631G>A	p.Arg1544Gln	missense	Exon 35 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.4610G>A	p.Arg1537Gln	missense	Exon 35 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.4631G>A	p.Arg1544Gln	missense	Exon 35 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000461872.6	TSL:1	n.4828G>A		non_coding_transcript_exon	Exon 33 of 55

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00192 AC: 483 AN: 251334 AF XY: 0.00246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000971 AC: 1419 AN: 1461830 Hom.: 22 Cov.: 32 AF XY: 0.00139 AC XY: 1013 AN XY: 727218

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0154 AC: 1331 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

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

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111966

Other (OTH) AF: 0.00108 AC: 65 AN: 60392

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74450

African (AFR) AF: 0.0000963 AC: 4 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.042
Sift	Benign	0.063	T
Sift4G	Benign	0.18	T
Polyphen		0.050	B
Vest4		0.20
MutPred		0.35		Loss of MoRF binding (P = 0.0515)
MVP		0.25
MPC		0.16
ClinPred		0.034	T
GERP RS		3.9
Varity_R		0.051
gMVP		0.11
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs369775705; hg19: chr6-152751696;