rs1058402

chr19-44647342-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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 -14 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 criteria_provided_single_submitter, 1 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	UniProt
PVR	NM_006505.5	c.199G>A	p.Ala67Thr	missense_variant	2/8	ENST00000425690.8
PVR	NM_001135770.4	c.199G>A	p.Ala67Thr	missense_variant	2/6
PVR	NM_001135768.3	c.199G>A	p.Ala67Thr	missense_variant	2/8
PVR	NM_001135769.3	c.199G>A	p.Ala67Thr	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PVR	ENST00000425690.8	c.199G>A	p.Ala67Thr	missense_variant	2/8	1	NM_006505.5	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: criteria provided, single submitter

Submissions by phenotype

PVR-related disorder Benign:1

Benign, criteria provided, single submitter

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
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;