20-2403658-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_198994.3(TGM6):​c.1171G>C​(p.Val391Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,461,872 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V391M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.35
Variant links:
Genes affected
TGM6 (HGNC:16255): (transglutaminase 6) The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.819
BS2
High AC in GnomAdExome4 at 45 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
TGM6NM_198994.3 linkc.1171G>C p.Val391Leu missense_variant Exon 9 of 13 ENST00000202625.7 NP_945345.2 O95932-1
TGM6NM_001254734.2 linkc.1171G>C p.Val391Leu missense_variant Exon 9 of 12 NP_001241663.1 O95932-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGM6ENST00000202625.7 linkc.1171G>C p.Val391Leu missense_variant Exon 9 of 13 1 NM_198994.3 ENSP00000202625.2 O95932-1
TGM6ENST00000381423.1 linkc.1171G>C p.Val391Leu missense_variant Exon 9 of 12 1 ENSP00000370831.1 O95932-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251454
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461872
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.0000396
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 04, 2021
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.074
T;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-2.2
N;N
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.018
D;D
Polyphen
1.0
D;D
Vest4
0.68
MutPred
0.61
Loss of catalytic residue at V391 (P = 0.031);Loss of catalytic residue at V391 (P = 0.031);
MVP
0.66
MPC
0.33
ClinPred
0.77
D
GERP RS
4.9
Varity_R
0.43
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs116904482; hg19: chr20-2384304; API