rs3771475

Variant names:

• chr2-70542196-T-C
• rs3771475
• NM_003236.4:c.40+11532A>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.40+11532A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,140 control chromosomes in the GnomAD database, including 1,491 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 0.12 (1491 hom., cov: 32)
• Consequence: TGFA NM_003236.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266
• Publications: 6 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.40+11532A>G		intron_variant	Intron 1 of 5	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.58+10988A>G		intron_variant	Intron 1 of 5		NP_001295087.1
TGFA	NM_001308159.2	c.58+10988A>G		intron_variant	Intron 1 of 5		NP_001295088.1
TGFA	NM_001099691.3	c.40+11532A>G		intron_variant	Intron 1 of 5		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.40+11532A>G		intron_variant	Intron 1 of 5	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18390 AN: 152022 Hom.: 1484 Cov.: 32

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.121 AC: 18401 AN: 152140 Hom.: 1491 Cov.: 32 AF XY: 0.129 AC XY: 9608 AN XY: 74378

African (AFR) AF: 0.0567 AC: 2353 AN: 41522

American (AMR) AF: 0.241 AC: 3685 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3464

East Asian (EAS) AF: 0.254 AC: 1313 AN: 5162

South Asian (SAS) AF: 0.292 AC: 1409 AN: 4818

European-Finnish (FIN) AF: 0.139 AC: 1469 AN: 10582

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7207 AN: 68006

Other (OTH) AF: 0.128 AC: 271 AN: 2116

Alfa AF: 0.117 Hom.: 781

Bravo AF: 0.123

Asia WGS AF: 0.257 AC: 891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.5
DANN	Benign	0.43
PhyloP100		0.27
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: rs3771475; hg19: chr2-70769328;