rs2166975

Variant names:

• chr2-70450862-G-A
• rs2166975
• NM_003236.4:c.480C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003236.4(TGFA):​c.480C>T​(p.Val160Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,607,768 control chromosomes in the GnomAD database, including 57,977 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 0.23 (4518 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53459 hom.)
• Consequence: TGFA NM_003236.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 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.480C>T	p.Val160Val	synonymous	Exon 6 of 6	NP_003227.1
	TGFA	NM_001308158.2		c.498C>T	p.Val166Val	synonymous	Exon 6 of 6	NP_001295087.1
	TGFA	NM_001308159.2		c.495C>T	p.Val165Val	synonymous	Exon 6 of 6	NP_001295088.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFA	ENST00000295400.11	TSL:1 MANE Select	c.480C>T	p.Val160Val	synonymous	Exon 6 of 6	ENSP00000295400.6
	TGFA	ENST00000444975.5	TSL:1	c.498C>T	p.Val166Val	synonymous	Exon 6 of 6	ENSP00000404131.1
	TGFA	ENST00000450929.5	TSL:1	c.495C>T	p.Val165Val	synonymous	Exon 6 of 6	ENSP00000414127.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35557 AN: 151954 Hom.: 4510 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.240 AC: 58120 AN: 242456 AF XY: 0.244

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.267 AC: 388789 AN: 1455696 Hom.: 53459 Cov.: 33 AF XY: 0.266 AC XY: 192735 AN XY: 723506

African (AFR) AF: 0.150 AC: 5015 AN: 33428

American (AMR) AF: 0.115 AC: 5098 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5487 AN: 25830

East Asian (EAS) AF: 0.280 AC: 11109 AN: 39646

South Asian (SAS) AF: 0.222 AC: 18865 AN: 84994

European-Finnish (FIN) AF: 0.310 AC: 16450 AN: 53090

Middle Eastern (MID) AF: 0.177 AC: 1020 AN: 5756

European-Non Finnish (NFE) AF: 0.280 AC: 310596 AN: 1108584

Other (OTH) AF: 0.252 AC: 15149 AN: 60144

GnomAD4 genome AF: 0.234 AC: 35575 AN: 152072 Hom.: 4518 Cov.: 32 AF XY: 0.234 AC XY: 17378 AN XY: 74332

African (AFR) AF: 0.162 AC: 6732 AN: 41524

American (AMR) AF: 0.155 AC: 2365 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1537 AN: 5162

South Asian (SAS) AF: 0.229 AC: 1101 AN: 4808

European-Finnish (FIN) AF: 0.309 AC: 3260 AN: 10544

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19027 AN: 67958

Other (OTH) AF: 0.234 AC: 494 AN: 2112

Alfa AF: 0.247 Hom.: 6699

Bravo AF: 0.220

Asia WGS AF: 0.287 AC: 999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.4
DANN	Benign	0.66
PhyloP100		2.0
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: rs2166975; hg19: chr2-70677994; COSMIC: COSV54912701;