16-31473920-C-G

Variant names:

• chr16-31473920-C-G
• rs140328458
• NM_001042454.3:c.268C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001042454.3(TGFB1I1):​c.268C>G​(p.Leu90Val) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TGFB1I1 NM_001042454.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.114490986).
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1I1	NM_001042454.3	c.268C>G	p.Leu90Val	missense_variant	Exon 4 of 11	ENST00000394863.8	NP_001035919.1
TGFB1I1	NM_001164719.1	c.217C>G	p.Leu73Val	missense_variant	Exon 4 of 11		NP_001158191.1
TGFB1I1	NM_015927.5	c.217C>G	p.Leu73Val	missense_variant	Exon 4 of 11		NP_057011.2
TGFB1I1	XM_024450412.2	c.217C>G	p.Leu73Val	missense_variant	Exon 4 of 11		XP_024306180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1I1	ENST00000394863.8	c.268C>G	p.Leu90Val	missense_variant	Exon 4 of 11	1	NM_001042454.3	ENSP00000378332.3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251310 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.000184 AC XY: 134 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>G (p.L90V) alteration is located in exon 4 (coding exon 4) of the TGFB1I1 gene. This alteration results from a C to G substitution at nucleotide position 268, causing the leucine (L) at amino acid position 90 to be replaced by a valine (V). 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	0.60
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;.;.;.;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	.;M;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;N;N;N;D;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;T;D;T;D;T;T
Sift4G	Uncertain	0.019	D;T;D;T;D;T;T
Polyphen		0.28	.;B;.;.;.;.;.
Vest4		0.32, 0.33, 0.33
MVP		0.61
MPC		0.12
ClinPred		0.20	T
GERP RS		4.9
Varity_R		0.23
gMVP		0.61

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: rs140328458; hg19: chr16-31485241;