Variant chr2-105269690-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004257.6(TGFBRAP1):c.1988C>A(p.Ala663Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TGFBRAP1
NM_004257.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Variant links:

Genes affected

TGFBRAP1 (HGNC:16836): (transforming growth factor beta receptor associated protein 1) This gene encodes a protein that binds to transforming growth factor-beta (TGF-beta) receptors and plays a role in TGF-beta signaling. The encoded protein acts as a chaprone in signaling downstream of TGF-beta. It is involved in signal-dependent association with SMAD4. The protein is also a component of mammalian CORVET, a multisubunit tethering protein complex that is involved in fusion of early endosomes. [provided by RefSeq, Jun 2016]

TGFBRAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1220572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBRAP1	NM_004257.6 link	c.1988C>A	p.Ala663Asp	missense_variant	11/12	ENST00000393359.7	NP_004248.2	Q8WUH2
TGFBRAP1	NM_001142621.3 link	c.1988C>A	p.Ala663Asp	missense_variant	11/12		NP_001136093.1	Q8WUH2
TGFBRAP1	NM_001426428.1 link	c.1988C>A	p.Ala663Asp	missense_variant	11/13		NP_001413357.1
TGFBRAP1	NM_001328646.3 link	c.1988C>A	p.Ala663Asp	missense_variant	11/12		NP_001315575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBRAP1	ENST00000393359.7 link	c.1988C>A	p.Ala663Asp	missense_variant	11/12	1	NM_004257.6	ENSP00000377027.2		Q8WUH2
TGFBRAP1	ENST00000595531.5 link	c.1988C>A	p.Ala663Asp	missense_variant	10/11	1		ENSP00000471434.2		Q8WUH2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1394082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684182

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.1988C>A (p.A663D) alteration is located in exon 11 (coding exon 10) of the TGFBRAP1 gene. This alteration results from a C to A substitution at nucleotide position 1988, causing the alanine (A) at amino acid position 663 to be replaced by an aspartic acid (D). 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

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.070

T;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

T;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.65

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.59

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.18

.;T;T

Sift4G

Uncertain

0.056

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.14

MutPred

0.41

Loss of catalytic residue at A663 (P = 0.0678);Loss of catalytic residue at A663 (P = 0.0678);Loss of catalytic residue at A663 (P = 0.0678);

MVP

0.35

MPC

0.45

ClinPred

0.56

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.14

gMVP

0.37

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over