rs3771523

Variant names:

• chr2-70450336-C-T
• rs3771523
• NM_003236.4:c.*523G>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.*523G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,746 control chromosomes in the GnomAD database, including 1,767 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 0.14 (1754 hom., cov: 32)
  • Exomes 𝑓: 0.15 (13 hom.)
• Consequence: TGFA NM_003236.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.27
• Publications: 8 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 (AMR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6		NP_001295087.1
TGFA	NM_001308159.2	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6		NP_001295088.1
TGFA	NM_001099691.3	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_003236.4	ENSP00000295400.6
TGFA	ENST00000418333.6	c.*523G>A		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000404099.2
TGFA	ENST00000445399.5	c.*19-715G>A		intron_variant	Intron 6 of 6	1		ENSP00000387493.1
TGFA	ENST00000419940.5	c.377-715G>A		intron_variant	Intron 3 of 3	5		ENSP00000407432.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20983 AN: 151970 Hom.: 1753 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.150 AC: 99 AN: 658 Hom.: 13 Cov.: 0 AF XY: 0.157 AC XY: 56 AN XY: 356

African (AFR) AF: 0.0556 AC: 1 AN: 18

American (AMR) AF: 0.311 AC: 28 AN: 90

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 1 AN: 12

East Asian (EAS) AF: 0.200 AC: 4 AN: 20

South Asian (SAS) AF: 0.150 AC: 3 AN: 20

European-Finnish (FIN) AF: 0.250 AC: 6 AN: 24

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.110 AC: 49 AN: 446

Other (OTH) AF: 0.250 AC: 7 AN: 28

GnomAD4 genome AF: 0.138 AC: 20998 AN: 152088 Hom.: 1754 Cov.: 32 AF XY: 0.144 AC XY: 10687 AN XY: 74332

African (AFR) AF: 0.107 AC: 4439 AN: 41458

American (AMR) AF: 0.268 AC: 4097 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3464

East Asian (EAS) AF: 0.167 AC: 862 AN: 5166

South Asian (SAS) AF: 0.169 AC: 813 AN: 4816

European-Finnish (FIN) AF: 0.189 AC: 2002 AN: 10580

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8028 AN: 68004

Other (OTH) AF: 0.132 AC: 278 AN: 2114

Alfa AF: 0.148 Hom.: 801

Bravo AF: 0.145

Asia WGS AF: 0.163 AC: 570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.51
PhyloP100		-3.3
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: rs3771523; hg19: chr2-70677468;