2-70453253-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003236.4(TGFA):​c.440T>A​(p.Leu147Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

TGFA
NM_003236.4 missense

Scores

2
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGFANM_003236.4 linkuse as main transcriptc.440T>A p.Leu147Gln missense_variant 5/6 ENST00000295400.11 NP_003227.1
TGFANM_001308158.2 linkuse as main transcriptc.458T>A p.Leu153Gln missense_variant 5/6 NP_001295087.1
TGFANM_001308159.2 linkuse as main transcriptc.455T>A p.Leu152Gln missense_variant 5/6 NP_001295088.1
TGFANM_001099691.3 linkuse as main transcriptc.437T>A p.Leu146Gln missense_variant 5/6 NP_001093161.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGFAENST00000295400.11 linkuse as main transcriptc.440T>A p.Leu147Gln missense_variant 5/61 NM_003236.4 ENSP00000295400 P4P01135-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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.:
30
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 13, 2022The c.440T>A (p.L147Q) alteration is located in exon 5 (coding exon 5) of the TGFA gene. This alteration results from a T to A substitution at nucleotide position 440, causing the leucine (L) at amino acid position 147 to be replaced by a glutamine (Q). 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
0.16
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;.;.;.;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.86
D;D;D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Uncertain
0.72
D;D;D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.
MutationTaster
Benign
0.99
D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.5
N;N;N;N;N
REVEL
Benign
0.24
Sift
Pathogenic
0.0
D;T;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;D;D;D;D
Vest4
0.83
MutPred
0.48
.;.;.;.;Gain of catalytic residue at L153 (P = 0.0179);
MVP
0.59
MPC
0.81
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.65
gMVP
0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1227430130; hg19: chr2-70680385; API