NM_145202.5:c.325C>A

Variant names:

• chr10-133352309-C-A
• rs1452539379
• NM_145202.5:c.325C>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.325C>A​(p.His109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRAP1 NM_145202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.128

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=0.0772495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAP1	NM_145202.5	c.325C>A	p.His109Asn	missense_variant	Exon 5 of 5	ENST00000433452.6	NP_660203.3
ZNF511-PRAP1	NM_001396060.1	c.997C>A	p.His333Asn	missense_variant	Exon 9 of 9		NP_001382989.1
PRAP1	NM_001145201.2	c.298C>A	p.His100Asn	missense_variant	Exon 5 of 5		NP_001138673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAP1	ENST00000433452.6	c.325C>A	p.His109Asn	missense_variant	Exon 5 of 5	1	NM_145202.5	ENSP00000416126.2
ZNF511-PRAP1	ENST00000368554.8	c.823C>A	p.His275Asn	missense_variant	Exon 8 of 8	2		ENSP00000357542.5
PRAP1	ENST00000463201.2	c.298C>A	p.His100Asn	missense_variant	Exon 5 of 5	1		ENSP00000486265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460876 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325C>A (p.H109N) alteration is located in exon 5 (coding exon 5) of the PRAP1 gene. This alteration results from a C to A substitution at nucleotide position 325, causing the histidine (H) at amino acid position 109 to be replaced by an asparagine (N). 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	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.5
DANN	Benign	0.67
DEOGEN2	Benign	0.063	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.012
Sift	Benign	0.32	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.26	B;.
Vest4		0.12
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0249);.;
MVP		0.014
MPC		0.25
ClinPred		0.083	T
GERP RS		-0.70
Varity_R		0.18
gMVP		0.040

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: rs1452539379; hg19: chr10-135165813;