2-70456428-A-G

Variant names:

• chr2-70456428-A-G
• rs140020331
• NM_003236.4:c.276T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_003236.4(TGFA):​c.276T>C​(p.Ala92Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,603,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: TGFA NM_003236.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.088).
• BP6: Variant 2-70456428-A-G is Benign according to our data. Variant chr2-70456428-A-G is described in ClinVar as [Benign]. Clinvar id is 746325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BS2: High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFA	NM_003236.4	c.276T>C	p.Ala92Ala	synonymous_variant	Exon 4 of 6	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.294T>C	p.Ala98Ala	synonymous_variant	Exon 4 of 6		NP_001295087.1
TGFA	NM_001308159.2	c.291T>C	p.Ala97Ala	synonymous_variant	Exon 4 of 6		NP_001295088.1
TGFA	NM_001099691.3	c.273T>C	p.Ala91Ala	synonymous_variant	Exon 4 of 6		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.276T>C	p.Ala92Ala	synonymous_variant	Exon 4 of 6	1	NM_003236.4	ENSP00000295400.6

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000250 AC: 58 AN: 231892 AF XY: 0.000216

Gnomad AFR exome AF: 0.00337

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 210 AN: 1451516 Hom.: 2 Cov.: 31 AF XY: 0.0000999 AC XY: 72 AN XY: 720956

African (AFR) AF: 0.00491 AC: 163 AN: 33204

American (AMR) AF: 0.000297 AC: 13 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39010

South Asian (SAS) AF: 0.00 AC: 0 AN: 83796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52576

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5748

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107582

Other (OTH) AF: 0.000350 AC: 21 AN: 59974

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152382 Hom.: 0 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74516

African (AFR) AF: 0.00370 AC: 154 AN: 41604

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000724 Hom.: 0

Bravo AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 17, 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	-0.85
CADD	Benign	4.2
DANN	Benign	0.56
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs140020331; hg19: chr2-70683560;