rs113463533

Variant names:

• chr15-43260162-G-A
• rs113463533
• NM_201631.4:c.326C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000220420.10(TGM5):​c.326C>T​(p.Thr109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,614,134 control chromosomes in the GnomAD database, including 178 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (19 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (159 hom.)
• Consequence: TGM5 ENST00000220420.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.540
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• acral peeling skin syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024375916).
• BP6: Variant 15-43260162-G-A is Benign according to our data. Variant chr15-43260162-G-A is described in ClinVar as Benign. ClinVar VariationId is 137639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000220420.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM5	NM_201631.4	MANE Select	c.326C>T	p.Thr109Met	missense	Exon 3 of 13	NP_963925.2
	TGM5	NM_004245.4		c.190+238C>T		intron	N/A	NP_004236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM5	ENST00000220420.10	TSL:1 MANE Select	c.326C>T	p.Thr109Met	missense	Exon 3 of 13	ENSP00000220420.5
	TGM5	ENST00000349114.8	TSL:1	c.190+238C>T		intron	N/A	ENSP00000220419.8

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152200 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0853

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00986 AC: 2476 AN: 251234 AF XY: 0.00939

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0856

Gnomad FIN exome AF: 0.00385

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00600 AC: 8770 AN: 1461816 Hom.: 159 Cov.: 32 AF XY: 0.00589 AC XY: 4282 AN XY: 727214

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.00514 AC: 230 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26136

East Asian (EAS) AF: 0.0817 AC: 3242 AN: 39700

South Asian (SAS) AF: 0.00268 AC: 231 AN: 86258

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53356

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5758

European-Non Finnish (NFE) AF: 0.00395 AC: 4392 AN: 1112012

Other (OTH) AF: 0.00662 AC: 400 AN: 60394

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152318 Hom.: 19 Cov.: 31 AF XY: 0.00659 AC XY: 491 AN XY: 74476

African (AFR) AF: 0.00108 AC: 45 AN: 41588

American (AMR) AF: 0.00562 AC: 86 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.0853 AC: 442 AN: 5180

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00649 Hom.: 25

Bravo AF: 0.00604

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00326

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Acral peeling skin syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.5
DANN	Benign	0.93
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-0.54
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Benign	0.20	T
Polyphen		0.015	B
Vest4		0.15
MVP		0.27
MPC		0.16
ClinPred		0.0011	T
GERP RS		-5.0
Varity_R		0.033
gMVP		0.28
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113463533; hg19: chr15-43552360; COSMIC: COSV55010176;