Genetic Variant PROCA1:p.Val191Leu (chr17-28704082-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001366301.1(PROCA1):c.571G>C(p.Val191Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,594,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V191M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PROCA1
NM_001366301.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.284

Publications

0 publications found

Variant links:

Genes affected

PROCA1 (HGNC:28600): (protein interacting with cyclin A1) Enables cyclin binding activity. Predicted to be involved in arachidonic acid secretion and phospholipid metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

PROCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035114408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROCA1	NM_001366301.1 link	c.571G>C	p.Val191Leu	missense_variant	Exon 5 of 5	ENST00000682792.1	NP_001353230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROCA1	ENST00000682792.1 link	c.571G>C	p.Val191Leu	missense_variant	Exon 5 of 5		NM_001366301.1	ENSP00000507242.1		A0A804HIV4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1442476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32220

American (AMR)

AF:

0.00

AC:

AN:

40026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25032

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

83408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105690

Other (OTH)

AF:

0.00

AC:

AN:

59442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41354

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

.;L

PhyloP100

0.28

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.51

N;.

REVEL

Benign

0.13

Sift

Benign

0.24

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.18

B;D

Vest4

0.065

MutPred

0.065

.;Gain of glycosylation at P188 (P = 0.1877);

MVP

0.10

MPC

0.089

ClinPred

0.25

GERP RS

1.9

Varity_R

0.022

gMVP

0.080

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over