16-31474232-C-G

Position:

• chr16-31474232-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042454.3(TGFB1I1):​c.406C>G​(p.Pro136Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFB1I1 NM_001042454.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.358

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 (HGNC:):

ACMG classification

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=0.08796325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1I1	NM_001042454.3	c.406C>G	p.Pro136Ala	missense_variant	5/11	ENST00000394863.8	NP_001035919.1
TGFB1I1	NM_001164719.1	c.355C>G	p.Pro119Ala	missense_variant	5/11		NP_001158191.1
TGFB1I1	NM_015927.5	c.355C>G	p.Pro119Ala	missense_variant	5/11		NP_057011.2
TGFB1I1	XM_024450412.2	c.355C>G	p.Pro119Ala	missense_variant	5/11		XP_024306180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1I1	ENST00000394863.8	c.406C>G	p.Pro136Ala	missense_variant	5/11	1	NM_001042454.3	ENSP00000378332.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.406C>G (p.P136A) alteration is located in exon 5 (coding exon 5) of the TGFB1I1 gene. This alteration results from a C to G substitution at nucleotide position 406, causing the proline (P) at amino acid position 136 to be replaced by an alanine (A). 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	0.055
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.067	T;T;.;.;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T;T;T;T;.;.
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.088	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.0010	.;B;.;.;.;.
Vest4		0.11, 0.11
MutPred		0.20		.;Loss of glycosylation at P136 (P = 0.023);.;.;.;.;
MVP		0.27
MPC		0.048
ClinPred		0.096	T
GERP RS		0.96
Varity_R		0.038
gMVP		0.35

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

Other links and lift over

dbSNP: rs202110011; hg19: chr16-31485553;