chr15-43234871-G-A

Position:

• chr15-43234871-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BS2_Supporting

The NM_201631.4(TGM5):​c.1773C>T​(p.Asp591=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.96

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]

ACMG classification

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/exons	MANE	UniProt
TGM5	NM_201631.4	c.1773C>T	p.Asp591=	synonymous_variant	11/13	ENST00000220420.10
TGM5	NM_004245.4	c.1527C>T	p.Asp509=	synonymous_variant	10/12
TGM5	XM_011522230.3	c.744C>T	p.Asp248=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM5	ENST00000220420.10	c.1773C>T	p.Asp591=	synonymous_variant	11/13	1	NM_201631.4	P1
TGM5	ENST00000349114.8	c.1527C>T	p.Asp509=	synonymous_variant	10/12	1
TGM5	ENST00000396996.3	n.1249C>T		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152248 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	TGM5: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Acral peeling skin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

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

Other links and lift over

dbSNP: rs142648722; hg19: chr15-43527069; COSMIC: COSV55008339; COSMIC: COSV55008339;