rs145911138

Variant names:

• chr6-152358383-C-T
• rs145911138
• NM_182961.4:c.10598G>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.10598G>A​(p.Arg3533His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,614,102 control chromosomes in the GnomAD database, including 306 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. R3533C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.018 (280 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.97
• Publications: 6 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=0.0023521185).
• BP6: Variant 6-152358383-C-T is Benign according to our data. Variant chr6-152358383-C-T is described in ClinVar as Benign. ClinVar VariationId is 130391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1870/152268) while in subpopulation NFE AF = 0.018 (1224/68030). AF 95% confidence interval is 0.0172. There are 26 homozygotes in GnomAd4. There are 881 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.10598G>A	p.Arg3533His	missense	Exon 66 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.10619G>A	p.Arg3540His	missense	Exon 66 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.10598G>A	p.Arg3533His	missense	Exon 66 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.10619G>A	p.Arg3540His	missense	Exon 66 of 146	ENSP00000396024.1
	SYNE1	ENST00000471834.1	TSL:1	n.3736G>A		non_coding_transcript_exon	Exon 9 of 19

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1871 AN: 152150 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0338

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.0125 AC: 3135 AN: 251466 AF XY: 0.0128

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0179 AC: 26129 AN: 1461834 Hom.: 280 Cov.: 31 AF XY: 0.0177 AC XY: 12840 AN XY: 727220

African (AFR) AF: 0.00287 AC: 96 AN: 33480

American (AMR) AF: 0.00438 AC: 196 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 698 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.0148 AC: 1278 AN: 86258

European-Finnish (FIN) AF: 0.0128 AC: 686 AN: 53416

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0198 AC: 22035 AN: 1111974

Other (OTH) AF: 0.0184 AC: 1111 AN: 60394

GnomAD4 genome AF: 0.0123 AC: 1870 AN: 152268 Hom.: 26 Cov.: 32 AF XY: 0.0118 AC XY: 881 AN XY: 74452

African (AFR) AF: 0.00366 AC: 152 AN: 41564

American (AMR) AF: 0.00458 AC: 70 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0338 AC: 117 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4828

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1224 AN: 68030

Other (OTH) AF: 0.0171 AC: 36 AN: 2104

Alfa AF: 0.0155 Hom.: 63

Bravo AF: 0.0114

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0118 AC: 1436

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 08, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive ataxia, Beauce type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.028
Sift	Benign	0.16	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.025	B
Vest4		0.23
MPC		0.17
ClinPred		0.0092	T
GERP RS		3.2
Varity_R		0.083
gMVP		0.072
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs145911138; hg19: chr6-152679518; COSMIC: COSV54946115;