rs606231278

Variant names:

• chr15-43234829-ACTGC-TGAAGGA
• rs606231278
• NM_201631.4:c.1811_1815delGCAGTinsTCCTTCA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_201631.4(TGM5):​c.1811_1815delGCAGTinsTCCTTCA​(p.Ser604IlefsTer9) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM5 NM_201631.4 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.84
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-43234829-ACTGC-TGAAGGA is Pathogenic according to our data. Variant chr15-43234829-ACTGC-TGAAGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 157571.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM5	NM_201631.4	c.1811_1815delGCAGTinsTCCTTCA	p.Ser604IlefsTer9	frameshift_variant, missense_variant	Exon 11 of 13	ENST00000220420.10	NP_963925.2
TGM5	NM_004245.4	c.1565_1569delGCAGTinsTCCTTCA	p.Ser522IlefsTer9	frameshift_variant, missense_variant	Exon 10 of 12		NP_004236.1
TGM5	XM_011522230.3	c.782_786delGCAGTinsTCCTTCA	p.Ser261IlefsTer9	frameshift_variant, missense_variant	Exon 5 of 7		XP_011520532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM5	ENST00000220420.10	c.1811_1815delGCAGTinsTCCTTCA	p.Ser604IlefsTer9	frameshift_variant, missense_variant	Exon 11 of 13	1	NM_201631.4	ENSP00000220420.5
TGM5	ENST00000349114.8	c.1565_1569delGCAGTinsTCCTTCA	p.Ser522IlefsTer9	frameshift_variant, missense_variant	Exon 10 of 12	1		ENSP00000220419.8
TGM5	ENST00000396996.3	n.1287_1291delGCAGTinsTCCTTCA		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acral peeling skin syndrome Pathogenic:1

Oct 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs606231278; hg19: chr15-43527027;