dbSNP rs759435542: TGFB1I1:p.Phe283Leu (chr16-31476146-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001042454.3(TGFB1I1):c.849C>G(p.Phe283Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TGFB1I1
NM_001042454.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

Variant links:

Genes affected

TGFB1I1 (HGNC:11767): (transforming growth factor beta 1 induced transcript 1) This gene encodes a coactivator of the androgen receptor, a transcription factor which is activated by androgen and has a key role in male sexual differentiation. The encoded protein is thought to regulate androgen receptor activity and may have a role to play in the treatment of prostate cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

TGFB1I1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1I1	NM_001042454.3 link	c.849C>G	p.Phe283Leu	missense_variant	Exon 8 of 11	ENST00000394863.8	NP_001035919.1	O43294-1
TGFB1I1	NM_001164719.1 link	c.798C>G	p.Phe266Leu	missense_variant	Exon 8 of 11		NP_001158191.1	O43294-2A0A024QZE7
TGFB1I1	NM_015927.5 link	c.798C>G	p.Phe266Leu	missense_variant	Exon 8 of 11		NP_057011.2	O43294-2A0A024QZE7
TGFB1I1	XM_024450412.2 link	c.798C>G	p.Phe266Leu	missense_variant	Exon 8 of 11		XP_024306180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1I1	ENST00000394863.8 link	c.849C>G	p.Phe283Leu	missense_variant	Exon 8 of 11	1	NM_001042454.3	ENSP00000378332.3		O43294-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250866

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461354

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.849C>G (p.F283L) alteration is located in exon 8 (coding exon 8) of the TGFB1I1 gene. This alteration results from a C to G substitution at nucleotide position 849, causing the phenylalanine (F) at amino acid position 283 to be replaced by a leucine (L). 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

Pathogenic

1.0

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

T;T;.;.

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.4

M;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.022

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.62

P;.;.;.

Vest4

0.68

MutPred

0.72

Loss of catalytic residue at F283 (P = 0.069);.;.;.;

MVP

0.69

MPC

1.2

ClinPred

0.79

GERP RS

4.5

Varity_R

0.66

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over