Genetic Variant RNPEP:p.Arg14Gln (chr1-201982707-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020216.4(RNPEP):c.41G>A(p.Arg14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,398,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

RNPEP
NM_020216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.127

Publications

2 publications found

Variant links:

Genes affected

RNPEP (HGNC:10078): (arginyl aminopeptidase) Predicted to enable metalloaminopeptidase activity. Predicted to be involved in proteolysis. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RNPEP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06773484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020216.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNPEP	NM_020216.4	MANE Select	c.41G>A	p.Arg14Gln	missense	Exon 1 of 11	NP_064601.3
RNPEP	NM_001319183.2		c.-827G>A		5_prime_UTR	Exon 1 of 10	NP_001306112.1
RNPEP	NM_001319184.2		c.-681G>A		5_prime_UTR	Exon 1 of 10	NP_001306113.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNPEP	ENST00000295640.9	TSL:1 MANE Select	c.41G>A	p.Arg14Gln	missense	Exon 1 of 11	ENSP00000295640.4	Q9H4A4
RNPEP	ENST00000967255.1		c.41G>A	p.Arg14Gln	missense	Exon 1 of 11	ENSP00000637314.1
RNPEP	ENST00000857425.1		c.41G>A	p.Arg14Gln	missense	Exon 1 of 11	ENSP00000527484.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.0000192

AC:

AN:

52128

AF XY:

0.0000333

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000613

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1246836

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

611792

show subpopulations

African (AFR)

AF:

0.000728

AC:

AN:

24722

American (AMR)

AF:

0.000114

AC:

AN:

17526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19604

East Asian (EAS)

AF:

0.0000369

AC:

AN:

27064

South Asian (SAS)

AF:

0.00

AC:

AN:

59006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.0000209

AC:

AN:

1002434

Other (OTH)

AF:

0.000100

AC:

AN:

49974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000112

AC:

AN:

151534

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67746

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000679

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.095

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.69

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

PhyloP100

0.13

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.34

REVEL

Benign

0.015

Sift

Benign

0.089

Sift4G

Benign

0.19

Polyphen

0.18

Vest4

0.052

MutPred

0.23

Gain of relative solvent accessibility (P = 0.09)

MVP

0.18

MPC

0.18

ClinPred

0.038

GERP RS

1.1

PromoterAI

0.058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.046

gMVP

0.36

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over