rs454305

Variant names:

• chr2-70509087-A-G
• rs454305
• NM_003236.4:c.94+5772T>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+5772T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,064 control chromosomes in the GnomAD database, including 15,815 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 0.43 (15815 hom., cov: 32)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 16 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 (AFR) allele frequency at 95% confidence interval = 0.651 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.94+5772T>C		intron	N/A	NP_003227.1	P01135-1
	TGFA	NM_001308158.2		c.112+5772T>C		intron	N/A	NP_001295087.1	F8VNR3
	TGFA	NM_001308159.2		c.112+5772T>C		intron	N/A	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.94+5772T>C		intron	N/A	ENSP00000295400.6	P01135-1
	TGFA	ENST00000444975.5	TSL:1	c.112+5772T>C		intron	N/A	ENSP00000404131.1	F8VNR3
	TGFA	ENST00000450929.5	TSL:1	c.112+5772T>C		intron	N/A	ENSP00000414127.1	E7EPT6

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65625 AN: 151946 Hom.: 15775 Cov.: 32

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.432 AC: 65710 AN: 152064 Hom.: 15815 Cov.: 32 AF XY: 0.430 AC XY: 31991 AN XY: 74328

African (AFR) AF: 0.657 AC: 27254 AN: 41480

American (AMR) AF: 0.385 AC: 5883 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 946 AN: 3464

East Asian (EAS) AF: 0.269 AC: 1394 AN: 5174

South Asian (SAS) AF: 0.374 AC: 1805 AN: 4822

European-Finnish (FIN) AF: 0.359 AC: 3779 AN: 10540

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23399 AN: 67980

Other (OTH) AF: 0.393 AC: 831 AN: 2112

Alfa AF: 0.365 Hom.: 44496

Bravo AF: 0.443

Asia WGS AF: 0.325 AC: 1135 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	9.0
DANN	Benign	0.45
PhyloP100		1.9
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: rs454305; hg19: chr2-70736219;