rs138617999

chr6-152428359-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_182961.4(SYNE1):c.4822G>A(p.Ala1608Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,960 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1608A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 0.319

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041214824).
• BP6: Variant 6-152428359-C-T is Benign according to our data. Variant chr6-152428359-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197018.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6, Benign=2}. Variant chr6-152428359-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.4822G>A	p.Ala1608Thr	missense_variant	37/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.4822G>A	p.Ala1608Thr	missense_variant	37/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.4843G>A	p.Ala1615Thr	missense_variant	37/146	1
SYNE1	ENST00000461872.6	n.5040G>A		non_coding_transcript_exon_variant	35/55	1
SYNE1	ENST00000367253.8	c.4822G>A	p.Ala1608Thr	missense_variant	35/36	5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000788 AC: 198 AN: 251218 Hom.: 1 AF XY: 0.000825 AC XY: 112 AN XY: 135756

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00152 AC: 2224 AN: 1461694 Hom.: 2 Cov.: 32 AF XY: 0.00143 AC XY: 1041 AN XY: 727136

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74466

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00147 Hom.: 1

Bravo AF: 0.00101

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.00224

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 13, 2019	The SYNE1 c.4843G>A; p.Ala1615Thr variant (rs138617999), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 197018). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (195/126496 alleles) in the Genome Aggregation Database. The alanine at codon 1615 is weakly conserved and is found as a threonine in multiple mammalian species, and computational analyses (SIFT: tolerated, PolyPhen-2: benign) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ala1615Thr variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2020	This variant is associated with the following publications: (PMID: 31692161) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 17, 2020	- -

Autosomal recessive ataxia, Beauce type Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 05, 2023

Variant summary: SYNE1 c.4843G>A (p.Ala1615Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 251218 control chromosomes in the gnomAD database, including 1 homozygote. c.4843G>A has been reported in the literature in at least one individual affected with ataxia without strong evidence for causality (e.g., Ngo_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31692161). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Four laboratories classified the variant as a variant of uncertain significance, three laboratories classified it as likely benign, one laboratory classified it as benign, and one laboratory classified it with conflicting interpretations (VUS/B). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1615 of the SYNE1 protein (p.Ala1615Thr). This variant is present in population databases (rs138617999, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 197018). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

SYNE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.8
Dann	Benign	0.50
DEOGEN2	Benign	0.072	T;.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.38	N;.;N;N
REVEL	Benign	0.021
Sift	Benign	0.70	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.047
MVP		0.14
MPC		0.13
ClinPred		0.0026	T
GERP RS		-1.3
Varity_R		0.032
gMVP		0.028

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138617999; hg19: chr6-152749494; COSMIC: COSV54940301;