2-70549252-T-C

Variant names:

• chr2-70549252-T-C
• rs12473408
• NM_003236.4:c.40+4476A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003236.4(TGFA):​c.40+4476A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,032 control chromosomes in the GnomAD database, including 18,842 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18842 hom., cov: 32)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

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.40+4476A>G		intron	N/A	NP_003227.1	P01135-1
	TGFA	NM_001308158.2		c.58+3932A>G		intron	N/A	NP_001295087.1	F8VNR3
	TGFA	NM_001308159.2		c.58+3932A>G		intron	N/A	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.40+4476A>G		intron	N/A	ENSP00000295400.6	P01135-1
	TGFA	ENST00000444975.5	TSL:1	c.58+3932A>G		intron	N/A	ENSP00000404131.1	F8VNR3
	TGFA	ENST00000450929.5	TSL:1	c.58+3932A>G		intron	N/A	ENSP00000414127.1	E7EPT6

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75044 AN: 151914 Hom.: 18805 Cov.: 32

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.470

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.494 AC: 75134 AN: 152032 Hom.: 18842 Cov.: 32 AF XY: 0.501 AC XY: 37193 AN XY: 74304

African (AFR) AF: 0.544 AC: 22532 AN: 41434

American (AMR) AF: 0.488 AC: 7462 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3468

East Asian (EAS) AF: 0.606 AC: 3140 AN: 5182

South Asian (SAS) AF: 0.492 AC: 2373 AN: 4820

European-Finnish (FIN) AF: 0.594 AC: 6270 AN: 10556

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30390 AN: 67966

Other (OTH) AF: 0.465 AC: 983 AN: 2114

Alfa AF: 0.458 Hom.: 17723

Bravo AF: 0.489

Asia WGS AF: 0.543 AC: 1887 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.22
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs12473408; hg19: chr2-70776384;