Genetic Variant NM_145202.5:c.374G>A (chr10-133352358-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145202.5(PRAP1):c.374G>A(p.Arg125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

PRAP1
NM_145202.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.606

Variant links:

Genes affected

PRAP1 (HGNC:23304): (proline rich acidic protein 1) Predicted to enable triglyceride binding activity. Involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; deactivation of mitotic spindle assembly checkpoint; and negative regulation of apoptotic process. Predicted to be located in endoplasmic reticulum and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PRAP1 links:

ZNF511-PRAP1 (HGNC:38088): (ZNF511-PRAP1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ZNF511 (zinc finger protein 511) and PRAP1 (proline-rich acidic protein 1) genes on chromosome 10. The putative readthrough transcript may encode a fusion protein that shares sequence identity with each individual gene product and may be involved in the regulation of gene promoters, particularly those found on transfected plasmids. [provided by RefSeq, Apr 2017]

ZNF511-PRAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027655631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAP1	NM_145202.5 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 5 of 5	ENST00000433452.6	NP_660203.3	Q96NZ9-1
ZNF511-PRAP1	NM_001396060.1 link	c.1046G>A	p.Arg349Lys	missense_variant	Exon 9 of 9		NP_001382989.1
PRAP1	NM_001145201.2 link	c.347G>A	p.Arg116Lys	missense_variant	Exon 5 of 5		NP_001138673.1	Q96NZ9-4A6XND8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRAP1	ENST00000433452.6 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 5 of 5	1	NM_145202.5	ENSP00000416126.2	Q96NZ9-1
ZNF511-PRAP1	ENST00000368554.8 link	c.872G>A	p.Arg291Lys	missense_variant	Exon 8 of 8	2		ENSP00000357542.5	H7BY64
PRAP1	ENST00000463201.2 link	c.347G>A	p.Arg116Lys	missense_variant	Exon 5 of 5	1		ENSP00000486265.1	Q96NZ9-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>A (p.R125K) alteration is located in exon 5 (coding exon 5) of the PRAP1 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a lysine (K). 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

0.059

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.080

DANN

Benign

0.53

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.19

T;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PROVEAN

Benign

-0.84

N;.

REVEL

Benign

0.025

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.012

B;.

Vest4

0.080

MutPred

0.15

Gain of ubiquitination at R125 (P = 0.0039);.;

MVP

0.014

MPC

0.21

ClinPred

0.031

GERP RS

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.079

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