Genetic Variant NM_003236.4:c.40+8140T>C (chr2-70545588-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003236.4(TGFA):c.40+8140T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,188 control chromosomes in the GnomAD database, including 2,744 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 0.17 ( 2744 hom., cov: 32)

Consequence

TGFA
NM_003236.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.228

Publications

5 publications found

Variant links:

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

TGFA links:

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new If you want to explore the variant's impact on the transcript NM_003236.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFA	NM_003236.4	MANE Select	c.40+8140T>C	intron	N/A	NP_003227.1	P01135-1
TGFA	NM_001308158.2		c.58+7596T>C	intron	N/A	NP_001295087.1	F8VNR3
TGFA	NM_001308159.2		c.58+7596T>C	intron	N/A	NP_001295088.1	E7EPT6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFA	ENST00000295400.11	TSL:1 MANE Select	c.40+8140T>C	intron	N/A	ENSP00000295400.6	P01135-1
TGFA	ENST00000444975.5	TSL:1	c.58+7596T>C	intron	N/A	ENSP00000404131.1	F8VNR3
TGFA	ENST00000450929.5	TSL:1	c.58+7596T>C	intron	N/A	ENSP00000414127.1	E7EPT6

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25549

AN:

152070

Hom.:

2746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0759

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.0830

Gnomad EAS

AF:

0.357

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.146

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

GnomAD4 genome

AF:

0.168

AC:

25541

AN:

152188

Hom.:

2744

Cov.:

AF XY:

0.174

AC XY:

12976

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0757

AC:

3147

AN:

41562

American (AMR)

AF:

0.120

AC:

1829

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

288

AN:

3470

East Asian (EAS)

AF:

0.357

AC:

1852

AN:

5184

South Asian (SAS)

AF:

0.141

AC:

682

AN:

4826

European-Finnish (FIN)

AF:

0.353

AC:

3725

AN:

10542

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.198

AC:

13495

AN:

67992

Other (OTH)

AF:

0.143

AC:

303

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1058

2116

3173

4231

5289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.185

Hom.:

11482

Bravo

AF:

0.147

Asia WGS

AF:

0.217

AC:

753

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.55

(source)

DANN

Benign

0.73

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over