rs1058402

Positions:

• chr19-44647342-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006505.5(PVR):​c.199G>A​(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.059 in 1,613,098 control chromosomes in the GnomAD database, including 4,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.058 (331 hom., cov: 30)
  • Exomes 𝑓: 0.059 (3724 hom.)
• Consequence: PVR NM_006505.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.55

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013558567).
• BP6: Variant 19-44647342-G-A is Benign according to our data. Variant chr19-44647342-G-A is described in ClinVar as [Benign]. Clinvar id is 3056684.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PVR	NM_006505.5	c.199G>A	p.Ala67Thr	missense_variant	2/8	ENST00000425690.8	NP_006496.4
PVR	NM_001135770.4	c.199G>A	p.Ala67Thr	missense_variant	2/6		NP_001129242.2
PVR	NM_001135768.3	c.199G>A	p.Ala67Thr	missense_variant	2/8		NP_001129240.1
PVR	NM_001135769.3	c.199G>A	p.Ala67Thr	missense_variant	2/7		NP_001129241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PVR	ENST00000425690.8	c.199G>A	p.Ala67Thr	missense_variant	2/8	1	NM_006505.5	ENSP00000402060	P2
CEACAM16-AS1	ENST00000662585.1	n.476-14723C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8821 AN: 152138 Hom.: 331 Cov.: 30

Gnomad AFR AF: 0.0630

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0774 AC: 19250 AN: 248850 Hom.: 1056 AF XY: 0.0788 AC XY: 10607 AN XY: 134626

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.0836

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0618

GnomAD4 exome AF: 0.0591 AC: 86357 AN: 1460842 Hom.: 3724 Cov.: 32 AF XY: 0.0620 AC XY: 45049 AN XY: 726638

Gnomad4 AFR exome AF: 0.0634

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0840

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.0472

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0580 AC: 8830 AN: 152256 Hom.: 331 Cov.: 30 AF XY: 0.0599 AC XY: 4459 AN XY: 74444

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.0653

Gnomad4 ASJ AF: 0.0767

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0457

Gnomad4 NFE AF: 0.0439

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0508 Hom.: 562

Bravo AF: 0.0589

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0545 AC: 210

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.0486 AC: 418

ExAC AF: 0.0770 AC: 9344

Asia WGS AF: 0.137 AC: 475 AN: 3478

EpiCase AF: 0.0426

EpiControl AF: 0.0418

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PVR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.023
DANN	Benign	0.70
DEOGEN2	Benign	0.0053	T;.;.;T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.44	T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	.;N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.48	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.76	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.013
MPC		0.34
ClinPred		0.0042	T
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1058402; hg19: chr19-45150614; COSMIC: COSV51823239; COSMIC: COSV51823239;