rs1554721227

chr6-152449536-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_182961.4(SYNE1):c.3499_3500del(p.Val1167Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE1 NM_182961.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.438

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-152449536-AAC-A is Pathogenic according to our data. Variant chr6-152449536-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 465780.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.3499_3500del	p.Val1167Ter	frameshift_variant	28/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.3499_3500del	p.Val1167Ter	frameshift_variant	28/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2016

This sequence change deletes 2 nucleotides from exon 28 of the SYNE1 mRNA (c.3520_3521delGT), causing a frameshift at codon 1174. This creates a premature translational stop signal (p.Val1174*) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in SYNE1 are known to cause autosomal recessive spinocerebellar ataxia (PMID: 17159980). In addition, missense sequence changes in SYNE1 have been reported in individuals affected with autosomal dominant EDMD or EDMD-like disease (PMID: 25091525, 17761684), but these observations are not expected to be relevant to truncating variants. -

Autosomal recessive ataxia, Beauce type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2016

This sequence change deletes 2 nucleotides from exon 28 of the SYNE1 mRNA (c.3520_3521delGT), causing a frameshift at codon 1174. This creates a premature translational stop signal (p.Val1174*) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in SYNE1 are known to cause autosomal recessive spinocerebellar ataxia (PMID: 17159980). In addition, missense sequence changes in SYNE1 have been reported in individuals affected with autosomal dominant EDMD or EDMD-like disease (PMID: 25091525, 17761684), but these observations are not expected to be relevant to truncating variants. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554721227; hg19: chr6-152770671;