NM_021635.3:c.218T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021635.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBOV1	NM_021635.3	MANE Select	c.218T>C	p.Ile73Thr	missense	Exon 1 of 1	NP_067648.1
	ARFGEF3	NM_020340.5	MANE Select	c.351+8137A>G		intron	N/A	NP_065073.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBOV1	ENST00000527246.3	TSL:6 MANE Select	c.218T>C	p.Ile73Thr	missense	Exon 1 of 1	ENSP00000432353.1
	ARFGEF3	ENST00000251691.5	TSL:1 MANE Select	c.351+8137A>G		intron	N/A	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

GnomAD2 exomes AF: 0.119 AC: 29765 AN: 250946 AF XY: 0.108

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 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

African (AFR) AF: 0.160 AC: 5371 AN: 33478

American (AMR) AF: 0.207 AC: 9269 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1754 AN: 26130

East Asian (EAS) AF: 0.359 AC: 14254 AN: 39684

South Asian (SAS) AF: 0.0626 AC: 5397 AN: 86248

European-Finnish (FIN) AF: 0.111 AC: 5928 AN: 53400

Middle Eastern (MID) AF: 0.0626 AC: 361 AN: 5768

European-Non Finnish (NFE) AF: 0.0668 AC: 74298 AN: 1111828

Other (OTH) AF: 0.0892 AC: 5383 AN: 60366

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

African (AFR) AF: 0.156 AC: 6495 AN: 41536

American (AMR) AF: 0.137 AC: 2089 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1856 AN: 5162

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4828

European-Finnish (FIN) AF: 0.114 AC: 1212 AN: 10592

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4729 AN: 68018

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.0869 Hom.: 2362

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 v4.9

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
PhyloP100		-3.9
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
PromoterAI		0.031	Neutral
Varity_R		0.31
gMVP		0.0031
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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