19-44647286-C-T

Position:

• chr19-44647286-C-T

Variant summary

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

The NM_006505.5(PVR):​c.143C>T​(p.Pro48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,431,274 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PVR NM_006505.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.143

Genes affected

PVR (HGNC:9705): (PVR cell adhesion molecule) The protein encoded by this gene is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. The external domain mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1/DYNLT1. The gene is specific to the primate lineage, and serves as a cellular receptor for poliovirus in the first step of poliovirus replication. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

PVR (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
PVR	NM_006505.5	c.143C>T	p.Pro48Leu	missense_variant	2/8	ENST00000425690.8	NP_006496.4
PVR	NM_001135770.4	c.143C>T	p.Pro48Leu	missense_variant	2/6		NP_001129242.2
PVR	NM_001135768.3	c.143C>T	p.Pro48Leu	missense_variant	2/8		NP_001129240.1
PVR	NM_001135769.3	c.143C>T	p.Pro48Leu	missense_variant	2/7		NP_001129241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PVR	ENST00000425690.8	c.143C>T	p.Pro48Leu	missense_variant	2/8	1	NM_006505.5	ENSP00000402060.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1431274 Hom.: 0 Cov.: 32 AF XY: 0.00000564 AC XY: 4 AN XY: 708986

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

Jul 25, 2024

The c.143C>T (p.P48L) alteration is located in exon 2 (coding exon 2) of the PVR gene. This alteration results from a C to T substitution at nucleotide position 143, causing the proline (P) at amino acid position 48 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	.;M;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.99, 1.0	.;D;D;.
Vest4		0.31
MutPred		0.70		Loss of catalytic residue at P48 (P = 0.0287);Loss of catalytic residue at P48 (P = 0.0287);Loss of catalytic residue at P48 (P = 0.0287);Loss of catalytic residue at P48 (P = 0.0287);
MVP		0.76
MPC		1.0
ClinPred		0.90	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1973150285; hg19: chr19-45150558;