chr15-43233593-A-G

Position:

chr15-43233593-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201631.4(TGM5):c.1970T>C(p.Val657Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,216 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 23 hom. )

Consequence

TGM5
NM_201631.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.09

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]

TGM5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006996453).

BP6

Variant 15-43233593-A-G is Benign according to our data. Variant chr15-43233593-A-G is described in ClinVar as [Benign]. Clinvar id is 887461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00886 (1349/152322) while in subpopulation AFR AF= 0.0314 (1304/41562). AF 95% confidence interval is 0.03. There are 16 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TGM5	NM_201631.4 linkuse as main transcript	c.1970T>C	p.Val657Ala	missense_variant	12/13	ENST00000220420.10
TGM5	NM_004245.4 linkuse as main transcript	c.1724T>C	p.Val575Ala	missense_variant	11/12
TGM5	XM_011522230.3 linkuse as main transcript	c.941T>C	p.Val314Ala	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM5	ENST00000220420.10 linkuse as main transcript	c.1970T>C	p.Val657Ala	missense_variant	12/13	1	NM_201631.4	P1	O43548-1
TGM5	ENST00000349114.8 linkuse as main transcript	c.1724T>C	p.Val575Ala	missense_variant	11/12	1			O43548-2
TGM5	ENST00000396996.3 linkuse as main transcript	n.1446T>C		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1349

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00222

AC:

559

AN:

251488

Hom.:

AF XY:

0.00165

AC XY:

224

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0321

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000820

AC:

1199

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

515

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0307

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00886

AC:

1349

AN:

152322

Hom.:

Cov.:

AF XY:

0.00834

AC XY:

621

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0314

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.00991

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TGM5: BP4, BS1, BS2 -

Acral peeling skin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

TGM5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2024

This variant is classified as 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

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

T;T;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.70

T;T;T;T;T

MetaRNN

Benign

0.0070

T;T;T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.2

.;.;M;.;.

MutationTaster

Benign

0.56

N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.9

.;.;D;.;D

REVEL

Uncertain

0.35

Sift

Benign

0.12

.;.;T;.;T

Sift4G

Benign

0.094

T;T;T;T;T

Polyphen

0.14, 0.85

.;.;B;.;P

Vest4

0.26, 0.27

MVP

0.48

MPC

0.30

ClinPred

0.068

GERP RS

5.9

Varity_R

0.23

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over