chr15-43233225-C-T

Position:

• chr15-43233225-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_201631.4(TGM5):​c.2129G>A​(p.Gly710Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM5 NM_201631.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM5	NM_201631.4	c.2129G>A	p.Gly710Asp	missense_variant	13/13	ENST00000220420.10
TGM5	NM_004245.4	c.1883G>A	p.Gly628Asp	missense_variant	12/12
TGM5	XM_011522230.3	c.1100G>A	p.Gly367Asp	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM5	ENST00000220420.10	c.2129G>A	p.Gly710Asp	missense_variant	13/13	1	NM_201631.4	P1
TGM5	ENST00000349114.8	c.1883G>A	p.Gly628Asp	missense_variant	12/12	1
TGM5	ENST00000396996.3	n.1605G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.2129G>A (p.G710D) alteration is located in exon 13 (coding exon 13) of the TGM5 gene. This alteration results from a G to A substitution at nucleotide position 2129, causing the glycine (G) at amino acid position 710 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.5	.;.;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	.;.;D;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	.;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;.;D;.;D
Vest4		0.80, 0.88
MutPred		0.86		.;.;Loss of MoRF binding (P = 0.0397);.;.;
MVP		0.78
MPC		0.74
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-43525423;