NM_003236.4:c.63G>A

Variant names:

• chr2-70514890-C-T
• rs10183171
• NM_003236.4:c.63G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003236.4(TGFA):​c.63G>A​(p.Gln21Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,614,062 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (26 hom.)
• Consequence: TGFA NM_003236.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.207
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-70514890-C-T is Benign according to our data. Variant chr2-70514890-C-T is described in ClinVar as [Benign]. Clinvar id is 787233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.207 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00875 (1333/152340) while in subpopulation AFR AF = 0.0302 (1256/41572). AF 95% confidence interval is 0.0288. There are 16 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1333 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.63G>A	p.Gln21Gln	synonymous_variant	Exon 2 of 6	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.81G>A	p.Gln27Gln	synonymous_variant	Exon 2 of 6		NP_001295087.1
TGFA	NM_001308159.2	c.81G>A	p.Gln27Gln	synonymous_variant	Exon 2 of 6		NP_001295088.1
TGFA	NM_001099691.3	c.63G>A	p.Gln21Gln	synonymous_variant	Exon 2 of 6		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.63G>A	p.Gln21Gln	synonymous_variant	Exon 2 of 6	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1329 AN: 152222 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00248 AC: 622 AN: 250656 AF XY: 0.00197

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000938 AC: 1371 AN: 1461722 Hom.: 26 Cov.: 31 AF XY: 0.000803 AC XY: 584 AN XY: 727144

African (AFR) AF: 0.0309 AC: 1036 AN: 33476

American (AMR) AF: 0.00192 AC: 86 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111978

Other (OTH) AF: 0.00219 AC: 132 AN: 60386

GnomAD4 genome AF: 0.00875 AC: 1333 AN: 152340 Hom.: 16 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74490

African (AFR) AF: 0.0302 AC: 1256 AN: 41572

American (AMR) AF: 0.00398 AC: 61 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00421 Hom.: 13

Bravo AF: 0.00991

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.4
DANN	Benign	0.86
PhyloP100		-0.21
Mutation Taster		=99/1	polymorphism

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: rs10183171; hg19: chr2-70742022;