15-43232939-G-A

Position:

• chr15-43232939-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201631.4(TGM5):​c.*252C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 514,540 control chromosomes in the GnomAD database, including 679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (520 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (159 hom.)
• Consequence: TGM5 NM_201631.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.984

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 15-43232939-G-A is Benign according to our data. Variant chr15-43232939-G-A is described in ClinVar as [Benign]. Clinvar id is 316035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM5	NM_201631.4	c.*252C>T		3_prime_UTR_variant	13/13	ENST00000220420.10
TGM5	NM_004245.4	c.*252C>T		3_prime_UTR_variant	12/12
TGM5	XM_011522230.3	c.*252C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM5	ENST00000220420.10	c.*252C>T		3_prime_UTR_variant	13/13	1	NM_201631.4	P1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6825 AN: 152148 Hom.: 511 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.00802 AC: 2904 AN: 362274 Hom.: 159 Cov.: 3 AF XY: 0.00723 AC XY: 1388 AN XY: 191924

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.00859

Gnomad4 ASJ exome AF: 0.00246

Gnomad4 EAS exome AF: 0.0260

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0451 AC: 6863 AN: 152266 Hom.: 520 Cov.: 32 AF XY: 0.0424 AC XY: 3154 AN XY: 74464

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0348 Hom.: 33

Bravo AF: 0.0522

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acral peeling skin syndrome Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7176183; hg19: chr15-43525137;