chr3-44901888-G-A

Position:

• chr3-44901888-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000296125.9(TGM4):​c.928G>A​(p.Glu310Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGM4 ENST00000296125.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

Genes affected

TGM4 (HGNC:11780): (transglutaminase 4) Predicted to enable protein-glutamine gamma-glutamyltransferase activity. Predicted to be involved in peptide cross-linking. Predicted to act upstream of or within mating plug formation. Located in Golgi apparatus and collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38128215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM4	NM_003241.4	c.928G>A	p.Glu310Lys	missense_variant	8/14	ENST00000296125.9	NP_003232.2
TGM4	XM_011534042.3	c.1063G>A	p.Glu355Lys	missense_variant	9/15		XP_011532344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM4	ENST00000296125.9	c.928G>A	p.Glu310Lys	missense_variant	8/14	1	NM_003241.4	ENSP00000296125.4
TGM4	ENST00000705784.1	c.1063G>A	p.Glu355Lys	missense_variant	9/15			ENSP00000516167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.928G>A (p.E310K) alteration is located in exon 8 (coding exon 8) of the TGM4 gene. This alteration results from a G to A substitution at nucleotide position 928, causing the glutamic acid (E) at amino acid position 310 to be replaced by a lysine (K). 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	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.26
Sift	Benign	0.068	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.18
MutPred		0.53		Gain of ubiquitination at E310 (P = 0.0146);
MVP		0.55
MPC		0.37
ClinPred		0.94	D
GERP RS		1.8
Varity_R		0.22
gMVP		0.37

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: chr3-44943380;