19-44649983-C-T

Variant names:

• chr19-44649983-C-T
• NM_006505.5:c.602C>T

Variant summary

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

The NM_006505.5(PVR):​c.602C>T​(p.Thr201Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PVR NM_006505.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.342

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, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PVR	NM_006505.5	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 8	ENST00000425690.8	NP_006496.4
PVR	NM_001135770.4	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 6		NP_001129242.2
PVR	NM_001135768.3	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 8		NP_001129240.1
PVR	NM_001135769.3	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 7		NP_001129241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PVR	ENST00000425690.8	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 8	1	NM_006505.5	ENSP00000402060.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455442 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723220

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602C>T (p.T201I) alteration is located in exon 3 (coding exon 3) of the PVR gene. This alteration results from a C to T substitution at nucleotide position 602, causing the threonine (T) at amino acid position 201 to be replaced by an isoleucine (I). 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	0.66
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;T
Eigen	Benign	0.0040
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.89	D;T;T;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	4.1	.;H;H;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.43
MutPred		0.91		Loss of catalytic residue at T201 (P = 0.0756);Loss of catalytic residue at T201 (P = 0.0756);Loss of catalytic residue at T201 (P = 0.0756);Loss of catalytic residue at T201 (P = 0.0756);
MVP		0.89
MPC		1.1
ClinPred		0.95	D
GERP RS		0.87
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45153255;