NM_201631.4:c.1891G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_201631.4(TGM5):ā€‹c.1891G>Cā€‹(p.Val631Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000029 ( 0 hom. )

Consequence

TGM5
NM_201631.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -2.62
Variant links:
Genes affected
TGM5 (HGNC:11781): (transglutaminase 5) This gene encodes a member of the transglutaminase family. The encoded protein catalyzes formation of protein cross-links between glutamine and lysine residues, often resulting in stabilization of protein assemblies. This reaction is calcium dependent. Mutations in this gene have been associated with acral peeling skin syndrome. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061740816).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGM5NM_201631.4 linkc.1891G>C p.Val631Leu missense_variant Exon 12 of 13 ENST00000220420.10 NP_963925.2 O43548-1B4DPS8
TGM5NM_004245.4 linkc.1645G>C p.Val549Leu missense_variant Exon 11 of 12 NP_004236.1 O43548-2B4DPS8
TGM5XM_011522230.3 linkc.862G>C p.Val288Leu missense_variant Exon 6 of 7 XP_011520532.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGM5ENST00000220420.10 linkc.1891G>C p.Val631Leu missense_variant Exon 12 of 13 1 NM_201631.4 ENSP00000220420.5 O43548-1
TGM5ENST00000349114.8 linkc.1645G>C p.Val549Leu missense_variant Exon 11 of 12 1 ENSP00000220419.8 O43548-2
TGM5ENST00000396996.3 linkn.1367G>C non_coding_transcript_exon_variant Exon 5 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000864
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:
0.0000557
AC:
14
AN:
251344
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00119
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:
0.0000294
AC:
43
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.000957
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.000864
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
Alfa
AF:
0.0000614
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Sep 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1891G>C (p.V631L) alteration is located in exon 12 (coding exon 12) of the TGM5 gene. This alteration results from a G to C substitution at nucleotide position 1891, causing the valine (V) at amino acid position 631 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Acral peeling skin syndrome Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
0.0080
DANN
Benign
0.57
DEOGEN2
Benign
0.023
T;T;T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.69
T;T;T;T;T
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.062
T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.2
.;.;L;.;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.83
.;.;N;.;N
REVEL
Benign
0.094
Sift
Benign
0.68
.;.;T;.;T
Sift4G
Benign
0.72
T;T;T;T;T
Polyphen
0.063, 0.022
.;.;B;.;B
Vest4
0.14, 0.14
MutPred
0.49
.;.;Loss of sheet (P = 0.0817);.;.;
MVP
0.27
MPC
0.15
ClinPred
0.78
D
GERP RS
-7.0
Varity_R
0.091
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs773549912; hg19: chr15-43525870; API