chr6-152330899-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):​c.13786T>A​(p.Ser4596Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,614,046 control chromosomes in the GnomAD database, including 473,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49272 hom., cov: 32)
Exomes 𝑓: 0.76 ( 424207 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.49
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=7.340609E-7).
BP6
Variant 6-152330899-A-T is Benign according to our data. Variant chr6-152330899-A-T is described in ClinVar as [Benign]. Clinvar id is 130404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330899-A-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.13786T>A p.Ser4596Thr missense_variant Exon 78 of 146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.13786T>A p.Ser4596Thr missense_variant Exon 78 of 146 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1
SYNE1ENST00000423061.6 linkc.13573T>A p.Ser4525Thr missense_variant Exon 77 of 146 1 ENSP00000396024.1 A0A0C4DG40
SYNE1ENST00000490135.6 linkn.1132T>A non_coding_transcript_exon_variant Exon 2 of 11 1

Frequencies

GnomAD3 genomes
AF:
0.802
AC:
121997
AN:
152102
Hom.:
49213
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.889
Gnomad AMI
AF:
0.717
Gnomad AMR
AF:
0.815
Gnomad ASJ
AF:
0.700
Gnomad EAS
AF:
0.847
Gnomad SAS
AF:
0.652
Gnomad FIN
AF:
0.845
Gnomad MID
AF:
0.652
Gnomad NFE
AF:
0.755
Gnomad OTH
AF:
0.766
GnomAD3 exomes
AF:
0.780
AC:
195948
AN:
251358
Hom.:
77245
AF XY:
0.766
AC XY:
104127
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.891
Gnomad AMR exome
AF:
0.867
Gnomad ASJ exome
AF:
0.712
Gnomad EAS exome
AF:
0.846
Gnomad SAS exome
AF:
0.647
Gnomad FIN exome
AF:
0.850
Gnomad NFE exome
AF:
0.756
Gnomad OTH exome
AF:
0.759
GnomAD4 exome
AF:
0.760
AC:
1110859
AN:
1461826
Hom.:
424207
Cov.:
65
AF XY:
0.755
AC XY:
549048
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.888
Gnomad4 AMR exome
AF:
0.861
Gnomad4 ASJ exome
AF:
0.714
Gnomad4 EAS exome
AF:
0.854
Gnomad4 SAS exome
AF:
0.650
Gnomad4 FIN exome
AF:
0.846
Gnomad4 NFE exome
AF:
0.755
Gnomad4 OTH exome
AF:
0.754
GnomAD4 genome
AF:
0.802
AC:
122114
AN:
152220
Hom.:
49272
Cov.:
32
AF XY:
0.805
AC XY:
59939
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.889
Gnomad4 AMR
AF:
0.815
Gnomad4 ASJ
AF:
0.700
Gnomad4 EAS
AF:
0.847
Gnomad4 SAS
AF:
0.651
Gnomad4 FIN
AF:
0.845
Gnomad4 NFE
AF:
0.755
Gnomad4 OTH
AF:
0.769
Alfa
AF:
0.760
Hom.:
32931
Bravo
AF:
0.806
TwinsUK
AF:
0.743
AC:
2756
ALSPAC
AF:
0.768
AC:
2958
ESP6500AA
AF:
0.887
AC:
3910
ESP6500EA
AF:
0.749
AC:
6441
ExAC
AF:
0.776
AC:
94209
Asia WGS
AF:
0.777
AC:
2704
AN:
3478
EpiCase
AF:
0.732
EpiControl
AF:
0.735

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 27, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
Nov 02, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1
Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.86
T
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.0010
DANN
Benign
0.20
DEOGEN2
Benign
0.085
T;.;T
Eigen
Benign
-2.8
Eigen_PC
Benign
-2.9
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.010
T;T;T
MetaRNN
Benign
7.3e-7
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.025
N;.;.
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.22
N;.;N
REVEL
Benign
0.049
Sift
Benign
0.57
T;.;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.089
MPC
0.12
ClinPred
0.024
T
GERP RS
-12
Varity_R
0.039
gMVP
0.057

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: rs6911096; hg19: chr6-152652034; COSMIC: COSV54944634; COSMIC: COSV54944634; API