rs6927706

Variant names:

• chr6-138218178-A-G
• rs6927706
• NM_021635.3:c.218T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021635.3(PBOV1):​c.218T>C​(p.Ile73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0863 in 1,613,830 control chromosomes in the GnomAD database, including 8,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1313 hom., cov: 32)
  • Exomes 𝑓: 0.083 (7515 hom.)
• Consequence: PBOV1 NM_021635.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.88

Genes affected

PBOV1 (HGNC:21079): (prostate and breast cancer overexpressed 1) This intronless gene encodes a protein of unknown function. Its expression is up-regulated in some types of cancer, including prostate, breast, and bladder cancer. [provided by RefSeq, Aug 2011]

ARFGEF3 (HGNC:21213): (ARFGEF family member 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in actin cytoskeleton organization. Predicted to be located in transport vesicle membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019096434).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBOV1	NM_021635.3	c.218T>C	p.Ile73Thr	missense_variant	Exon 1 of 1	ENST00000527246.3	NP_067648.1
ARFGEF3	NM_020340.5	c.351+8137A>G		intron_variant	Intron 4 of 33	ENST00000251691.5	NP_065073.3
ARFGEF3	XR_001743524.2	n.499+8137A>G		intron_variant	Intron 4 of 34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBOV1	ENST00000527246.3	c.218T>C	p.Ile73Thr	missense_variant	Exon 1 of 1	6	NM_021635.3	ENSP00000432353.1
ARFGEF3	ENST00000251691.5	c.351+8137A>G		intron_variant	Intron 4 of 33	1	NM_020340.5	ENSP00000251691.4

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17135 AN: 152088 Hom.: 1296 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.0995

GnomAD3 exomes AF: 0.119 AC: 29765 AN: 250946 Hom.: 2884 AF XY: 0.108 AC XY: 14686 AN XY: 135612

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.0609

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0930

GnomAD4 exome AF: 0.0835 AC: 122015 AN: 1461624 Hom.: 7515 Cov.: 31 AF XY: 0.0818 AC XY: 59461 AN XY: 727094

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.0626

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0668

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.113 AC: 17189 AN: 152206 Hom.: 1313 Cov.: 32 AF XY: 0.115 AC XY: 8580 AN XY: 74406

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.0694

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0695

Gnomad4 OTH AF: 0.0994

Alfa AF: 0.0826 Hom.: 1580

Bravo AF: 0.121

TwinsUK AF: 0.0766 AC: 284

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.152 AC: 668

ESP6500EA AF: 0.0685 AC: 589

ExAC AF: 0.112 AC: 13624

Asia WGS AF: 0.180 AC: 625 AN: 3478

EpiCase AF: 0.0631

EpiControl AF: 0.0580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0020
DANN	Benign	0.31
DEOGEN2	Benign	0.036	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00076	N
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.14
Polyphen		0.0	B
Vest4		0.0070
MPC		0.0043
ClinPred		0.024	T
GERP RS		-6.2
Varity_R		0.31
gMVP		0.0031

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

LitVar

Other links and lift over

dbSNP: rs6927706; hg19: chr6-138539315; COSMIC: COSV52450383;