rs748404

Variant names:

• chr15-43267033-T-C
• rs748404
• NM_201631.4:c.-184A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_201631.4(TGM5):​c.-184A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,266 control chromosomes in the GnomAD database, including 2,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (2735 hom., cov: 33)
• Consequence: TGM5 NM_201631.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51
• Publications: 31 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-43267033-T-C is Benign according to our data. Variant chr15-43267033-T-C is described in ClinVar as Benign. ClinVar VariationId is 1276897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM5	NM_201631.4	c.-184A>G		upstream_gene_variant		ENST00000220420.10	NP_963925.2
TGM5	NM_004245.4	c.-184A>G		upstream_gene_variant			NP_004236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM5	ENST00000220420.10	c.-184A>G		upstream_gene_variant		1	NM_201631.4	ENSP00000220420.5
TGM5	ENST00000349114.8	c.-184A>G		upstream_gene_variant		1		ENSP00000220419.8

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26692 AN: 152148 Hom.: 2735 Cov.: 33

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.175 AC: 26690 AN: 152266 Hom.: 2735 Cov.: 33 AF XY: 0.175 AC XY: 13017 AN XY: 74450

African (AFR) AF: 0.0895 AC: 3722 AN: 41574

American (AMR) AF: 0.225 AC: 3438 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 897 AN: 3472

East Asian (EAS) AF: 0.0412 AC: 214 AN: 5188

South Asian (SAS) AF: 0.270 AC: 1300 AN: 4820

European-Finnish (FIN) AF: 0.158 AC: 1679 AN: 10612

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14815 AN: 67990

Other (OTH) AF: 0.192 AC: 405 AN: 2114

Alfa AF: 0.210 Hom.: 12044

Bravo AF: 0.177

Asia WGS AF: 0.139 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.65
PhyloP100		1.5
PromoterAI		0.081	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748404; hg19: chr15-43559231;