Genetic Variant TGFA:p.Arg134Gly (chr2-70453293-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003236.4(TGFA):c.400C>G(p.Arg134Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TGFA
NM_003236.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.78

Publications

0 publications found

Variant links:

Genes affected

TGFA (HGNC:11765): (transforming growth factor alpha) This gene encodes a growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

TGFA Gene-Disease associations (from GenCC):

tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TGFA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3296609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4 link	c.400C>G	p.Arg134Gly	missense_variant	Exon 5 of 6	ENST00000295400.11	NP_003227.1	P01135-1
TGFA	NM_001308158.2 link	c.418C>G	p.Arg140Gly	missense_variant	Exon 5 of 6		NP_001295087.1	P01135F8VNR3
TGFA	NM_001308159.2 link	c.415C>G	p.Arg139Gly	missense_variant	Exon 5 of 6		NP_001295088.1	P01135E7EPT6
TGFA	NM_001099691.3 link	c.397C>G	p.Arg133Gly	missense_variant	Exon 5 of 6		NP_001093161.1	P01135-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11 link	c.400C>G	p.Arg134Gly	missense_variant	Exon 5 of 6	1	NM_003236.4	ENSP00000295400.6		P01135-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111904

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

T;T;T;T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.1

M;.;.;.;.

PhyloP100

4.8

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Benign

0.095

T;T;T;T;T

Polyphen

0.49

P;P;P;P;P

Vest4

0.60

MutPred

0.40

.;.;.;.;Loss of helix (P = 0.0444);

MVP

0.20

MPC

0.40

ClinPred

0.97

GERP RS

5.9

Varity_R

0.34

gMVP

0.60

Mutation Taster

=51/49

polymorphism

(source)

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

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2-70453293-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over