Genetic Variant TPRG1:p.Ile122Thr (chr3-189238795-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_198485.4(TPRG1):c.365T>C(p.Ile122Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TPRG1
NM_198485.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83

Variant links:

Genes affected

TPRG1 (HGNC:24759): (tumor protein p63 regulated 1) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TPRG1 links:

TPRG1-AS2 (HGNC:41062): (TPRG1 antisense RNA 2)

TPRG1-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRG1	NM_198485.4 link	c.365T>C	p.Ile122Thr	missense_variant	Exon 4 of 6	ENST00000345063.8	NP_940887.1	Q6ZUI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPRG1	ENST00000345063.8 link	c.365T>C	p.Ile122Thr	missense_variant	Exon 4 of 6	1	NM_198485.4	ENSP00000341031.3	Q6ZUI0
TPRG1	ENST00000433971.5 link	c.365T>C	p.Ile122Thr	missense_variant	Exon 9 of 11	2		ENSP00000412547.1	Q6ZUI0
TPRG1	ENST00000425670.1 link	c.146T>C	p.Ile49Thr	missense_variant	Exon 2 of 4	3		ENSP00000400171.1	H7C1G4
TPRG1-AS2	ENST00000425454.1 link	n.370A>G		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250904

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365T>C (p.I122T) alteration is located in exon 4 (coding exon 3) of the TPRG1 gene. This alteration results from a T to C substitution at nucleotide position 365, causing the isoleucine (I) at amino acid position 122 to be replaced by a threonine (T). 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

Uncertain

0.49

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.38

Sift

Benign

0.074

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.52

Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);

MVP

0.12

MPC

0.24

ClinPred

0.94

GERP RS

5.7

Varity_R

0.25

gMVP

0.80

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