2-70498220-A-G

Variant names:

• chr2-70498220-A-G
• rs3771494
• NM_003236.4:c.94+16639T>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.94+16639T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,216 control chromosomes in the GnomAD database, including 8,820 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 0.31 (8820 hom., cov: 33)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.94+16639T>C		intron_variant	Intron 2 of 5	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.112+16639T>C		intron_variant	Intron 2 of 5		NP_001295087.1
TGFA	NM_001308159.2	c.112+16639T>C		intron_variant	Intron 2 of 5		NP_001295088.1
TGFA	NM_001099691.3	c.94+16639T>C		intron_variant	Intron 2 of 5		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.94+16639T>C		intron_variant	Intron 2 of 5	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46901 AN: 152098 Hom.: 8794 Cov.: 33

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.309 AC: 46979 AN: 152216 Hom.: 8820 Cov.: 33 AF XY: 0.306 AC XY: 22813 AN XY: 74446

African (AFR) AF: 0.513 AC: 21301 AN: 41528

American (AMR) AF: 0.403 AC: 6167 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 771 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1118 AN: 5178

South Asian (SAS) AF: 0.296 AC: 1429 AN: 4828

European-Finnish (FIN) AF: 0.163 AC: 1732 AN: 10614

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13560 AN: 67998

Other (OTH) AF: 0.316 AC: 667 AN: 2112

Alfa AF: 0.246 Hom.: 15335

Bravo AF: 0.339

Asia WGS AF: 0.257 AC: 898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.5
DANN	Benign	0.74
PhyloP100		0.34
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: rs3771494; hg19: chr2-70725352;