15-43234871-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBS2_Supporting

The NM_201631.4(TGM5):​c.1773C>T​(p.Asp591Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.00318 in 1,614,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0033 ( 9 hom. )

Consequence

TGM5
NM_201631.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.96
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 Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 15-43234871-G-A is Benign according to our data. Variant chr15-43234871-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 316039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes 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
TGM5NM_201631.4 linkc.1773C>T p.Asp591Asp synonymous_variant Exon 11 of 13 ENST00000220420.10 NP_963925.2 O43548-1B4DPS8
TGM5NM_004245.4 linkc.1527C>T p.Asp509Asp synonymous_variant Exon 10 of 12 NP_004236.1 O43548-2B4DPS8
TGM5XM_011522230.3 linkc.744C>T p.Asp248Asp synonymous_variant Exon 5 of 7 XP_011520532.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGM5ENST00000220420.10 linkc.1773C>T p.Asp591Asp synonymous_variant Exon 11 of 13 1 NM_201631.4 ENSP00000220420.5 O43548-1
TGM5ENST00000349114.8 linkc.1527C>T p.Asp509Asp synonymous_variant Exon 10 of 12 1 ENSP00000220419.8 O43548-2
TGM5ENST00000396996.3 linkn.1249C>T non_coding_transcript_exon_variant Exon 4 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.00227
AC:
346
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000965
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.000850
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00417
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00234
AC:
589
AN:
251486
Hom.:
3
AF XY:
0.00238
AC XY:
324
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.00202
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000817
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.00400
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.00328
AC:
4791
AN:
1461876
Hom.:
9
Cov.:
32
AF XY:
0.00321
AC XY:
2332
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.00172
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000788
Gnomad4 FIN exome
AF:
0.000655
Gnomad4 NFE exome
AF:
0.00399
Gnomad4 OTH exome
AF:
0.00260
GnomAD4 genome
AF:
0.00227
AC:
346
AN:
152366
Hom.:
0
Cov.:
32
AF XY:
0.00227
AC XY:
169
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000962
Gnomad4 AMR
AF:
0.000849
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.00417
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00329
Hom.:
1
Bravo
AF:
0.00213
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00322
EpiControl
AF:
0.00302

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Dec 31, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TGM5: BP4, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Acral peeling skin syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

TGM5-related disorder Benign:1
Dec 15, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.43
CADD
Benign
10
DANN
Benign
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs142648722; hg19: chr15-43527069; COSMIC: COSV55008339; COSMIC: COSV55008339; API