TGM5 p.Lys445Asn

Variant names:

• chr15-43238827-C-A
• NM_201631.4:c.1335G>T
• TGM5 p.Lys445Asn

Your query was ambiguous. Multiple possible variants found:

• chr15-43238827-C-A
• chr15-43238827-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_201631.4(TGM5):​c.1335G>T​(p.Lys445Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM5 NM_201631.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• 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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

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.1335G>T	p.Lys445Asn	missense	Exon 9 of 13	NP_963925.2	O43548-1
	TGM5	NM_004245.4		c.1089G>T	p.Lys363Asn	missense	Exon 8 of 12	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.1335G>T	p.Lys445Asn	missense	Exon 9 of 13	ENSP00000220420.5	O43548-1
	TGM5	ENST00000349114.8	TSL:1	c.1089G>T	p.Lys363Asn	missense	Exon 8 of 12	ENSP00000220419.8	O43548-2
	TGM5	ENST00000396996.3	TSL:2	n.811G>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		0.19
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.83
gMVP		0.85

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

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

Other links and lift over

hg19: chr15-43531025;