2-70493471-C-T

Variant names:

• chr2-70493471-C-T
• rs3755378
• NM_003236.4:c.94+21388G>A

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+21388G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,030 control chromosomes in the GnomAD database, including 6,873 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 0.28 (6873 hom., cov: 32)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.746
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.94+21388G>A		intron_variant	Intron 2 of 5	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.112+21388G>A		intron_variant	Intron 2 of 5		NP_001295087.1
TGFA	NM_001308159.2	c.112+21388G>A		intron_variant	Intron 2 of 5		NP_001295088.1
TGFA	NM_001099691.3	c.94+21388G>A		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+21388G>A		intron_variant	Intron 2 of 5	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42147 AN: 151912 Hom.: 6868 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.277 AC: 42154 AN: 152030 Hom.: 6873 Cov.: 32 AF XY: 0.279 AC XY: 20695 AN XY: 74272

African (AFR) AF: 0.128 AC: 5317 AN: 41514

American (AMR) AF: 0.206 AC: 3150 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2035 AN: 5162

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4808

European-Finnish (FIN) AF: 0.424 AC: 4468 AN: 10534

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24277 AN: 67954

Other (OTH) AF: 0.269 AC: 569 AN: 2112

Alfa AF: 0.314 Hom.: 1038

Bravo AF: 0.257

Asia WGS AF: 0.316 AC: 1096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.77
DANN	Benign	0.66
PhyloP100		-0.75
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: rs3755378; hg19: chr2-70720603;