rs139671151

Positions:

• chr6-152141345-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.25120-16G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,613,292 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (83 hom.)
• Consequence: SYNE1 NM_182961.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0330

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-152141345-C-A is Benign according to our data. Variant chr6-152141345-C-A is described in ClinVar as [Benign]. Clinvar id is 262192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152141345-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00668 (1017/152278) while in subpopulation AMR AF= 0.0169 (259/15298). AF 95% confidence interval is 0.0152. There are 5 homozygotes in gnomad4. There are 521 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_001347702.2	c.1654-16G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000354674.5
SYNE1	NM_182961.4	c.25120-16G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000354674.5	c.1654-16G>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001347702.2
SYNE1	ENST00000367255.10	c.25120-16G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152160 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00719

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00822 AC: 2067 AN: 251400 Hom.: 19 AF XY: 0.00851 AC XY: 1157 AN XY: 135878

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00954

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00954

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00682 AC: 9957 AN: 1461014 Hom.: 83 Cov.: 32 AF XY: 0.00711 AC XY: 5166 AN XY: 726834

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00962

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00650

Gnomad4 OTH exome AF: 0.00923

GnomAD4 genome AF: 0.00668 AC: 1017 AN: 152278 Hom.: 5 Cov.: 32 AF XY: 0.00700 AC XY: 521 AN XY: 74456

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00719

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0102 Hom.: 1

Bravo AF: 0.00813

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2016	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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

SYNE1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139671151; hg19: chr6-152462480;