2-70449507-A-G

Variant names:

• chr2-70449507-A-G
• rs538118
• NM_003236.4:c.*1352T>C

Variant summary

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

The NM_003236.4(TGFA):​c.*1352T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 174,308 control chromosomes in the GnomAD database, including 11,056 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 0.34 (9217 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1839 hom.)
• Consequence: TGFA NM_003236.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 11 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.39 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.*1352T>C		3_prime_UTR	Exon 6 of 6	NP_003227.1	P01135-1
	TGFA	NM_001308158.2		c.*1352T>C		3_prime_UTR	Exon 6 of 6	NP_001295087.1	F8VNR3
	TGFA	NM_001308159.2		c.*1352T>C		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.*1352T>C		3_prime_UTR	Exon 6 of 6	ENSP00000295400.6	P01135-1
	TGFA	ENST00000445399.5	TSL:1	c.*133T>C		3_prime_UTR	Exon 7 of 7	ENSP00000387493.1	P01135-3
	TGFA	ENST00000869601.1		c.*1352T>C		3_prime_UTR	Exon 5 of 5	ENSP00000539660.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50988 AN: 151924 Hom.: 9223 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.367

GnomAD4 exome AF: 0.383 AC: 8531 AN: 22266 Hom.: 1839 Cov.: 0 AF XY: 0.389 AC XY: 4812 AN XY: 12374

African (AFR) AF: 0.197 AC: 157 AN: 796

American (AMR) AF: 0.331 AC: 368 AN: 1112

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 344 AN: 682

East Asian (EAS) AF: 0.331 AC: 286 AN: 864

South Asian (SAS) AF: 0.421 AC: 1328 AN: 3152

European-Finnish (FIN) AF: 0.303 AC: 478 AN: 1580

Middle Eastern (MID) AF: 0.513 AC: 875 AN: 1706

European-Non Finnish (NFE) AF: 0.378 AC: 4215 AN: 11158

Other (OTH) AF: 0.395 AC: 480 AN: 1216

GnomAD4 genome AF: 0.335 AC: 50994 AN: 152042 Hom.: 9217 Cov.: 32 AF XY: 0.332 AC XY: 24668 AN XY: 74320

African (AFR) AF: 0.222 AC: 9222 AN: 41486

American (AMR) AF: 0.350 AC: 5339 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1828 AN: 3468

East Asian (EAS) AF: 0.326 AC: 1688 AN: 5176

South Asian (SAS) AF: 0.404 AC: 1948 AN: 4818

European-Finnish (FIN) AF: 0.285 AC: 3009 AN: 10554

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26790 AN: 67956

Other (OTH) AF: 0.363 AC: 766 AN: 2112

Alfa AF: 0.378 Hom.: 21325

Bravo AF: 0.333

Asia WGS AF: 0.326 AC: 1132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.076
DANN	Benign	0.43
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs538118; hg19: chr2-70676639; COSMIC: COSV54915383; COSMIC: COSV54915383;