NM_201631.4:c.1940C>G

Variant names:

• chr15-43233623-G-C
• rs745436900
• NM_201631.4:c.1940C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201631.4(TGM5):​c.1940C>G​(p.Ser647Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TGM5 NM_201631.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22940564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM5	NM_201631.4	c.1940C>G	p.Ser647Trp	missense_variant	Exon 12 of 13	ENST00000220420.10	NP_963925.2
TGM5	NM_004245.4	c.1694C>G	p.Ser565Trp	missense_variant	Exon 11 of 12		NP_004236.1
TGM5	XM_011522230.3	c.911C>G	p.Ser304Trp	missense_variant	Exon 6 of 7		XP_011520532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM5	ENST00000220420.10	c.1940C>G	p.Ser647Trp	missense_variant	Exon 12 of 13	1	NM_201631.4	ENSP00000220420.5
TGM5	ENST00000349114.8	c.1694C>G	p.Ser565Trp	missense_variant	Exon 11 of 12	1		ENSP00000220419.8
TGM5	ENST00000396996.3	n.1416C>G		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T;T;T;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	.;.;L;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	.;.;D;.;D
REVEL	Benign	0.15
Sift	Benign	0.19	.;.;T;.;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.035, 0.11	.;.;B;.;B
Vest4		0.37, 0.37
MutPred		0.56		.;.;Loss of disorder (P = 0.0892);.;.;
MVP		0.23
MPC		0.21
ClinPred		0.37	T
GERP RS		-7.2
Varity_R		0.31
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs745436900; hg19: chr15-43525821;