6-152510340-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP3PP5_ModerateBS2_Supporting

The NM_182961.4(SYNE1):​c.434T>A​(p.Leu145His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

10
6
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.37
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.796
PP5
Variant 6-152510340-A-T is Pathogenic according to our data. Variant chr6-152510340-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522970.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.434T>A p.Leu145His missense_variant Exon 8 of 146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.434T>A p.Leu145His missense_variant Exon 8 of 146 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251228
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461748
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive ataxia, Beauce type Pathogenic:1
Dec 18, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;.;T;.;.;.;.;.;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.0
M;.;.;M;.;M;.;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.2
N;.;N;D;D;D;D;D;.
REVEL
Uncertain
0.62
Sift
Uncertain
0.0070
D;.;D;D;D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;.;D
Polyphen
1.0
D;.;.;.;.;.;D;.;.
Vest4
0.71
MutPred
0.22
Loss of catalytic residue at L145 (P = 0.0352);.;.;Loss of catalytic residue at L145 (P = 0.0352);.;Loss of catalytic residue at L145 (P = 0.0352);Loss of catalytic residue at L145 (P = 0.0352);Loss of catalytic residue at L145 (P = 0.0352);.;
MVP
0.96
MPC
0.68
ClinPred
0.90
D
GERP RS
5.7
Varity_R
0.39
gMVP
0.67

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755531859; hg19: chr6-152831475; API