Variant 3-44893634-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003241.4(TGM4):c.488C>T(p.Thr163Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,898 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

TGM4
NM_003241.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.563

Variant links:

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]

TGM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.36315897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM4	NM_003241.4 linkuse as main transcript	c.488C>T	p.Thr163Met	missense_variant	5/14	ENST00000296125.9	NP_003232.2
TGM4	XM_011534042.3 linkuse as main transcript	c.623C>T	p.Thr208Met	missense_variant	6/15		XP_011532344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TGM4	ENST00000296125.9 linkuse as main transcript	c.488C>T	p.Thr163Met	missense_variant	5/14	1	NM_003241.4	ENSP00000296125	P2
TGM4	ENST00000422219.5 linkuse as main transcript	c.*105C>T		3_prime_UTR_variant, NMD_transcript_variant	4/6	1		ENSP00000403711
TGM4	ENST00000705784.1 linkuse as main transcript	c.623C>T	p.Thr208Met	missense_variant	6/15			ENSP00000516167	A2
TGM4	ENST00000495844.1 linkuse as main transcript	n.452C>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251358

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.488C>T (p.T163M) alteration is located in exon 5 (coding exon 5) of the TGM4 gene. This alteration results from a C to T substitution at nucleotide position 488, causing the threonine (T) at amino acid position 163 to be replaced by a methionine (M). 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

-0.17

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.0068

M_CAP

Benign

0.039

MetaRNN

Benign

0.36

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Benign

0.093

Polyphen

1.0

Vest4

0.40

MutPred

0.50

Loss of disorder (P = 0.2277);

MVP

0.85

MPC

0.42

ClinPred

0.34

GERP RS

2.2

Varity_R

0.17

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over