chr2-70506394-T-C

Variant names:

• chr2-70506394-T-C
• rs404420
• NM_003236.4:c.94+8465A>G

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+8465A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,104 control chromosomes in the GnomAD database, including 43,207 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 0.75 (43207 hom., cov: 32)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 14 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFA	NM_003236.4	MANE Select	c.94+8465A>G		intron	N/A	NP_003227.1
	TGFA	NM_001308158.2		c.112+8465A>G		intron	N/A	NP_001295087.1
	TGFA	NM_001308159.2		c.112+8465A>G		intron	N/A	NP_001295088.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFA	ENST00000295400.11	TSL:1 MANE Select	c.94+8465A>G		intron	N/A	ENSP00000295400.6
	TGFA	ENST00000444975.5	TSL:1	c.112+8465A>G		intron	N/A	ENSP00000404131.1
	TGFA	ENST00000450929.5	TSL:1	c.112+8465A>G		intron	N/A	ENSP00000414127.1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113841 AN: 151986 Hom.: 43161 Cov.: 32

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.723

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

GnomAD4 genome AF: 0.749 AC: 113941 AN: 152104 Hom.: 43207 Cov.: 32 AF XY: 0.747 AC XY: 55519 AN XY: 74344

African (AFR) AF: 0.872 AC: 36226 AN: 41526

American (AMR) AF: 0.670 AC: 10236 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2047 AN: 3472

East Asian (EAS) AF: 0.777 AC: 4009 AN: 5162

South Asian (SAS) AF: 0.676 AC: 3247 AN: 4804

European-Finnish (FIN) AF: 0.733 AC: 7752 AN: 10578

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47979 AN: 67968

Other (OTH) AF: 0.727 AC: 1532 AN: 2108

Alfa AF: 0.709 Hom.: 63496

Bravo AF: 0.751

Asia WGS AF: 0.749 AC: 2603 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs404420; hg19: chr2-70733526;