19-44650054-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006505.5(PVR):c.673C>G(p.His225Asp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PVR NM_006505.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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]

CEACAM16-AS1 (HGNC:55317): (CEACAM16, CEACAM19 and PVR antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PVR	NM_006505.5	c.673C>G	p.His225Asp	missense_variant	3/8	ENST00000425690.8
PVR	NM_001135770.4	c.673C>G	p.His225Asp	missense_variant	3/6
PVR	NM_001135768.3	c.673C>G	p.His225Asp	missense_variant	3/8
PVR	NM_001135769.3	c.673C>G	p.His225Asp	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PVR	ENST00000425690.8	c.673C>G	p.His225Asp	missense_variant	3/8	1	NM_006505.5	P2
CEACAM16-AS1	ENST00000662585.1	n.476-17435G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Mar 20, 2023

The c.673C>G (p.H225D) alteration is located in exon 3 (coding exon 3) of the PVR gene. This alteration results from a C to G substitution at nucleotide position 673, causing the histidine (H) at amino acid position 225 to be replaced by an aspartic acid (D). 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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99, 0.94	.;D;P;.
Vest4		0.62
MutPred		0.72		Loss of methylation at K222 (P = 0.0643);Loss of methylation at K222 (P = 0.0643);Loss of methylation at K222 (P = 0.0643);Loss of methylation at K222 (P = 0.0643);
MVP		0.71
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45153326;