rs3732253

Variant names:

• chr2-70448966-G-A
• rs3732253
• NM_003236.4:c.*1893C>T

Variant summary

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

The NM_003236.4(TGFA):​c.*1893C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,122 control chromosomes in the GnomAD database, including 4,293 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 0.22 (4293 hom., cov: 33)
  • Exomes 𝑓: 0.20 (0 hom.)
• Consequence: TGFA NM_003236.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 13 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 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.*1893C>T		3_prime_UTR	Exon 6 of 6	NP_003227.1	P01135-1
	TGFA	NM_001308158.2		c.*1893C>T		3_prime_UTR	Exon 6 of 6	NP_001295087.1	F8VNR3
	TGFA	NM_001308159.2		c.*1893C>T		3_prime_UTR	Exon 6 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.*1893C>T		3_prime_UTR	Exon 6 of 6	ENSP00000295400.6	P01135-1
	TGFA	ENST00000869601.1		c.*1893C>T		3_prime_UTR	Exon 5 of 5	ENSP00000539660.1
	TGFA	ENST00000869602.1		c.*1893C>T		3_prime_UTR	Exon 5 of 5	ENSP00000539661.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34016 AN: 151994 Hom.: 4285 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.200 AC: 2 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 2 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 2 AN: 8

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.224 AC: 34029 AN: 152112 Hom.: 4293 Cov.: 33 AF XY: 0.224 AC XY: 16649 AN XY: 74352

African (AFR) AF: 0.125 AC: 5184 AN: 41512

American (AMR) AF: 0.153 AC: 2334 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3468

East Asian (EAS) AF: 0.298 AC: 1544 AN: 5176

South Asian (SAS) AF: 0.229 AC: 1107 AN: 4832

European-Finnish (FIN) AF: 0.308 AC: 3254 AN: 10548

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19076 AN: 67986

Other (OTH) AF: 0.223 AC: 471 AN: 2108

Alfa AF: 0.243 Hom.: 4961

Bravo AF: 0.208

Asia WGS AF: 0.286 AC: 996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.41
DANN	Benign	0.76
PhyloP100		-1.5
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: rs3732253; hg19: chr2-70676098;