chr10-133351429-G-A

Variant names:

• chr10-133351429-G-A
• rs1848676661
• NM_145202.5:c.124G>A

Variant summary

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

The NM_145202.5(PRAP1):​c.124G>A​(p.Glu42Lys) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRAP1 NM_145202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.699

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]

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]

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=0.13033706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAP1	NM_145202.5	c.124G>A	p.Glu42Lys	missense_variant	Exon 3 of 5	ENST00000433452.6	NP_660203.3
ZNF511-PRAP1	NM_001396060.1	c.796G>A	p.Glu266Lys	missense_variant	Exon 7 of 9		NP_001382989.1
PRAP1	NM_001145201.2	c.124G>A	p.Glu42Lys	missense_variant	Exon 3 of 5		NP_001138673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAP1	ENST00000433452.6	c.124G>A	p.Glu42Lys	missense_variant	Exon 3 of 5	1	NM_145202.5	ENSP00000416126.2
ZNF511-PRAP1	ENST00000368554.8	c.622G>A	p.Glu208Lys	missense_variant	Exon 6 of 8	2		ENSP00000357542.5
PRAP1	ENST00000463201.2	c.124G>A	p.Glu42Lys	missense_variant	Exon 3 of 5	1		ENSP00000486265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>A (p.E42K) alteration is located in exon 3 (coding exon 3) of the PRAP1 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the glutamic acid (E) at amino acid position 42 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	0.10
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PROVEAN	Uncertain	-3.6	D;.
REVEL	Benign	0.093
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.70	P;.
Vest4		0.23
MutPred		0.30		Gain of ubiquitination at E42 (P = 0.0109);Gain of ubiquitination at E42 (P = 0.0109);
MVP		0.040
MPC		0.26
ClinPred		0.47	T
GERP RS		1.9
Varity_R		0.30
gMVP		0.14

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: rs1848676661; hg19: chr10-135164933;