15-43252856-CCA-TCT

Variant names:

• chr15-43252856-CCA-TCT
• NM_201631.4:c.763_765delTGGinsAGA
• TGM5 p.Trp255Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Very_Strong PP3

The NM_201631.4(TGM5):​c.763_765delTGGinsAGA​(p.Trp255Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM5 NM_201631.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.23
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_201631.4 (TGM5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201631.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM5	NM_201631.4	MANE Select	c.763_765delTGGinsAGA	p.Trp255Arg	missense	N/A	NP_963925.2	O43548-1
	TGM5	NM_004245.4		c.517_519delTGGinsAGA	p.Trp173Arg	missense	N/A	NP_004236.1	O43548-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM5	ENST00000220420.10	TSL:1 MANE Select	c.763_765delTGGinsAGA	p.Trp255Arg	missense	N/A	ENSP00000220420.5	O43548-1
	TGM5	ENST00000349114.8	TSL:1	c.517_519delTGGinsAGA	p.Trp173Arg	missense	N/A	ENSP00000220419.8	O43548-2
	TGM5	ENST00000635871.1	TSL:4	n.232_234delTGGinsAGA		non_coding_transcript_exon	Exon 2 of 4

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-43545054;