Variant 3-44896807-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000296125.9(TGM4):c.648G>A(p.Met216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,926 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TGM4
ENST00000296125.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.146

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040391356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM4	NM_003241.4 linkuse as main transcript	c.648G>A	p.Met216Ile	missense_variant	6/14	ENST00000296125.9	NP_003232.2	P49221
TGM4	XM_011534042.3 linkuse as main transcript	c.783G>A	p.Met261Ile	missense_variant	7/15		XP_011532344.1	A0A994J576

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TGM4	ENST00000296125.9 linkuse as main transcript	c.648G>A	p.Met216Ile	missense_variant	6/14	1	NM_003241.4	ENSP00000296125.4	P49221
TGM4	ENST00000422219.5 linkuse as main transcript	n.*265G>A		non_coding_transcript_exon_variant	5/6	1		ENSP00000403711.1	F8WCU8
TGM4	ENST00000422219.5 linkuse as main transcript	n.*265G>A		3_prime_UTR_variant	5/6	1		ENSP00000403711.1	F8WCU8
TGM4	ENST00000705784.1 linkuse as main transcript	c.783G>A	p.Met261Ile	missense_variant	7/15			ENSP00000516167.1	A0A994J576

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251376

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Oct 22, 2021

The c.648G>A (p.M216I) alteration is located in exon 6 (coding exon 6) of the TGM4 gene. This alteration results from a G to A substitution at nucleotide position 648, causing the methionine (M) at amino acid position 216 to be replaced by an isoleucine (I). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Benign

3.3

DANN

Benign

0.79

DEOGEN2

Benign

0.042

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.022

M_CAP

Benign

0.021

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.84

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

0.19

REVEL

Benign

0.14

Sift

Benign

0.48

Sift4G

Benign

0.82

Polyphen

0.0080

Vest4

0.19

MutPred

0.35

Loss of catalytic residue at V212 (P = 0.0479);

MVP

0.61

MPC

0.089

ClinPred

0.023

GERP RS

-0.65

Varity_R

0.038

gMVP

0.16

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