rs1378400021

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_182961.4(SYNE1):​c.4524G>T​(p.Gln1508His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,996 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.181
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 Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24739918).
BS2
High AC in GnomAdExome4 at 9 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/exons MANE Protein UniProt
SYNE1NM_182961.4 linkc.4524G>T p.Gln1508His missense_variant 35/146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.4524G>T p.Gln1508His missense_variant 35/1461 NM_182961.4 ENSP00000356224.5 Q8NF91-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251384
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461822
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 16, 2024Variant summary: SYNE1 c.4545G>T (p.Gln1515His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4545G>T in individuals affected with SYNE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 448602). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJun 09, 2017- -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 13, 2021This sequence change replaces glutamine with histidine at codon 1515 of the SYNE1 protein (p.Gln1515His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. 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: "Benign"; 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
T;.;T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.89
D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.25
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.7
M;.;.;M
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-2.0
N;N;N;D
REVEL
Benign
0.17
Sift
Benign
0.098
T;D;T;D
Sift4G
Uncertain
0.0070
D;D;D;D
Polyphen
0.99
D;.;.;D
Vest4
0.28
MutPred
0.25
Loss of disorder (P = 0.0714);.;.;Loss of disorder (P = 0.0714);
MVP
0.51
MPC
0.13
ClinPred
0.80
D
GERP RS
3.9
Varity_R
0.076
gMVP
0.17

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: rs1378400021; hg19: chr6-152751782; API