Genetic Variant NM_020216.4:c.397G>C (chr1-201983063-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020216.4(RNPEP):c.397G>C(p.Ala133Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A133S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RNPEP
NM_020216.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.397

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088712454).

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.397G>C	p.Ala133Pro	missense	Exon 1 of 11	NP_064601.3
RNPEP	NM_001319183.2		c.-471G>C		5_prime_UTR	Exon 1 of 10	NP_001306112.1
RNPEP	NM_001319184.2		c.-325G>C		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.397G>C	p.Ala133Pro	missense	Exon 1 of 11	ENSP00000295640.4	Q9H4A4
RNPEP	ENST00000471105.5	TSL:1	n.109G>C		non_coding_transcript_exon	Exon 1 of 10
RNPEP	ENST00000967255.1		c.397G>C	p.Ala133Pro	missense	Exon 1 of 11	ENSP00000637314.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1373030

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28578

American (AMR)

AF:

0.00

AC:

AN:

32818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23796

East Asian (EAS)

AF:

0.00

AC:

AN:

32560

South Asian (SAS)

AF:

0.00

AC:

AN:

76786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4664

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1073918

Other (OTH)

AF:

0.00

AC:

AN:

56798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.081

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.57

M_CAP

Benign

0.018

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.20

PhyloP100

0.40

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

REVEL

Benign

0.027

Sift

Benign

0.090

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.088

MutPred

0.58

Gain of disorder (P = 0.1067)

MVP

0.23

MPC

0.29

ClinPred

0.26

GERP RS

0.45

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.19

gMVP

0.70

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over