chr2-70465703-T-C

Variant names:

• chr2-70465703-T-C
• rs782818852
• NM_003236.4:c.128A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003236.4(TGFA):​c.128A>G​(p.His43Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFA NM_003236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.128A>G	p.His43Arg	missense_variant	Exon 3 of 6	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.146A>G	p.His49Arg	missense_variant	Exon 3 of 6		NP_001295087.1
TGFA	NM_001308159.2	c.143A>G	p.His48Arg	missense_variant	Exon 3 of 6		NP_001295088.1
TGFA	NM_001099691.3	c.125A>G	p.His42Arg	missense_variant	Exon 3 of 6		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.128A>G	p.His43Arg	missense_variant	Exon 3 of 6	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128A>G (p.H43R) alteration is located in exon 3 (coding exon 3) of the TGFA gene. This alteration results from a A to G substitution at nucleotide position 128, causing the histidine (H) at amino acid position 43 to be replaced by an arginine (R). 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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.069	T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;.
Polyphen		0.38	B;B;B;P;B;.
Vest4		0.55
MutPred		0.71		.;.;.;.;Gain of helix (P = 0.062);.;
MVP		0.42
MPC		0.58
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		0.019	Neutral
Varity_R		0.71
gMVP		0.91
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs782818852; hg19: chr2-70692835;