rs199700477

Variant names:

• chr2-70465718-G-A
• rs199700477
• NM_003236.4:c.113C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-70465718-G-A
• chr2-70465718-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003236.4(TGFA):​c.113C>T​(p.Ala38Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 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. A38E) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3386935).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003236.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFA	NM_003236.4	MANE Select	c.113C>T	p.Ala38Val	missense	Exon 3 of 6	NP_003227.1	P01135-1
	TGFA	NM_001308158.2		c.131C>T	p.Ala44Val	missense	Exon 3 of 6	NP_001295087.1	F8VNR3
	TGFA	NM_001308159.2		c.128C>T	p.Ala43Val	missense	Exon 3 of 6	NP_001295088.1	E7EPT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFA	ENST00000295400.11	TSL:1 MANE Select	c.113C>T	p.Ala38Val	missense	Exon 3 of 6	ENSP00000295400.6	P01135-1
	TGFA	ENST00000444975.5	TSL:1	c.131C>T	p.Ala44Val	missense	Exon 3 of 6	ENSP00000404131.1	F8VNR3
	TGFA	ENST00000450929.5	TSL:1	c.128C>T	p.Ala43Val	missense	Exon 3 of 6	ENSP00000414127.1	E7EPT6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.20
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.34		Loss of disorder (P = 0.086)
MVP		0.22
MPC		0.79
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.69
Mutation Taster		=16/84	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: rs199700477; hg19: chr2-70692850;