2-70514871-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003236.4(TGFA):​c.82T>A​(p.Ser28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

TGFA
NM_003236.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1414046).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFANM_003236.4 linkc.82T>A p.Ser28Thr missense_variant Exon 2 of 6 ENST00000295400.11 NP_003227.1 P01135-1
TGFANM_001308158.2 linkc.100T>A p.Ser34Thr missense_variant Exon 2 of 6 NP_001295087.1 P01135F8VNR3
TGFANM_001308159.2 linkc.100T>A p.Ser34Thr missense_variant Exon 2 of 6 NP_001295088.1 P01135E7EPT6
TGFANM_001099691.3 linkc.82T>A p.Ser28Thr missense_variant Exon 2 of 6 NP_001093161.1 P01135-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFAENST00000295400.11 linkc.82T>A p.Ser28Thr missense_variant Exon 2 of 6 1 NM_003236.4 ENSP00000295400.6 P01135-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41432
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 03, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.82T>A (p.S28T) alteration is located in exon 2 (coding exon 2) of the TGFA gene. This alteration results from a T to A substitution at nucleotide position 82, causing the serine (S) at amino acid position 28 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
21
DANN
Benign
0.92
DEOGEN2
Benign
0.28
T;.;.;.;.;.
Eigen
Benign
-0.048
Eigen_PC
Benign
-0.076
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.70
T;T;T;T;T;T
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.14
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;L;L;.;.;.
PhyloP100
2.8
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.56
N;N;N;N;N;N
REVEL
Benign
0.050
Sift
Benign
0.28
T;T;T;T;T;T
Sift4G
Benign
0.27
T;T;T;T;T;.
Polyphen
0.86
P;B;B;D;D;.
Vest4
0.42
MutPred
0.27
.;.;.;Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);.;
MVP
0.32
MPC
0.20
ClinPred
0.76
D
GERP RS
4.0
Varity_R
0.084
gMVP
0.58
Mutation Taster
=90/10
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

Publications

Other links and lift over

dbSNP: rs1476246950; hg19: chr2-70742003; API