16-31474237-C-A

Position:

• chr16-31474237-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001042454.3(TGFB1I1):​c.411C>A​(p.Ser137Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFB1I1 NM_001042454.3 missense, splice_region
• Scores: Splicing: ADA: 0.006159
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667

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 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity TGFI1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17319933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1I1	NM_001042454.3	c.411C>A	p.Ser137Arg	missense_variant, splice_region_variant	5/11	ENST00000394863.8	NP_001035919.1
TGFB1I1	NM_001164719.1	c.360C>A	p.Ser120Arg	missense_variant, splice_region_variant	5/11		NP_001158191.1
TGFB1I1	NM_015927.5	c.360C>A	p.Ser120Arg	missense_variant, splice_region_variant	5/11		NP_057011.2
TGFB1I1	XM_024450412.2	c.360C>A	p.Ser120Arg	missense_variant, splice_region_variant	5/11		XP_024306180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1I1	ENST00000394863.8	c.411C>A	p.Ser137Arg	missense_variant, splice_region_variant	5/11	1	NM_001042454.3	ENSP00000378332.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 33

ExAC AF: 0.00000824 AC: 1

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

Jan 24, 2023

The c.411C>A (p.S137R) alteration is located in exon 5 (coding exon 5) of the TGFB1I1 gene. This alteration results from a C to A substitution at nucleotide position 411, causing the serine (S) at amino acid position 137 to be replaced by an arginine (R). 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	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T;T;T;T;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	D;N;N;N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.056	T;D;D;T;T;T
Polyphen		0.073	.;B;.;.;.;.
Vest4		0.15, 0.15
MutPred		0.32		.;Loss of phosphorylation at S137 (P = 6e-04);.;.;.;.;
MVP		0.46
MPC		0.057
ClinPred		0.57	D
GERP RS		4.2
Varity_R		0.11
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0062
dbscSNV1_RF	Benign	0.16
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

LitVar

Other links and lift over

dbSNP: rs761600660; hg19: chr16-31485558;