rs41291047

chr6-152135141-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_182961.4(SYNE1):c.25751A>C(p.Asp8584Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D8584G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2 O:1
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.41885594).
• BP6: Variant 6-152135141-T-G is Benign according to our data. Variant chr6-152135141-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194451.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=1, Likely_benign=1, Uncertain_significance=7}.
• BS2: High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.25751A>C	p.Asp8584Ala	missense_variant	142/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.2285A>C	p.Asp762Ala	missense_variant	14/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.25751A>C	p.Asp8584Ala	missense_variant	142/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.2285A>C	p.Asp762Ala	missense_variant	14/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000545 AC: 137 AN: 251444 Hom.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135894

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000923

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000611 AC: 893 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 440 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000728

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74494

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00117 Hom.: 3

Bravo AF: 0.000374

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2021	Observed with a variant on the opposite allele (in trans) in a patient with Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation in published literature; however, the patient also was compound heterozygous for two variants in another gene that may have been responsible for the phenotype (Barclay et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26302956) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SYNE1: BP1, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -

Autosomal recessive ataxia, Beauce type Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.25607A>C (p.D8536A) alteration is located in exon 142 (coding exon 141) of the SYNE1 gene. This alteration results from an A to C substitution at nucleotide position 25607, causing the aspartic acid (D) at amino acid position 8536 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.05% (152/282854) total alleles studied. The highest observed frequency was 0.09% (117/129158) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 8536 of the SYNE1 protein (p.Asp8536Ala). This variant is present in population databases (rs41291047, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 194451). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

SYNE1-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 03-06-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;T;T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.2	D;.;D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;.;D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;T;T;D;T;T
Polyphen		0.97	D;.;.;.;.;.;.
Vest4		0.78
MVP		0.74
MPC		0.66
ClinPred		0.22	T
GERP RS		6.2
Varity_R		0.58
gMVP		0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs41291047; hg19: chr6-152456276; COSMIC: COSV104533105;