Genetic Variant RNPEP:p.Glu35Gln (chr1-201982769-G-C) – 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_020216.4(RNPEP):c.103G>C(p.Glu35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. E35K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RNPEP
NM_020216.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.808

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: 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=0.044699967).

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.103G>C	p.Glu35Gln	missense	Exon 1 of 11	NP_064601.3
RNPEP	NM_001319183.2		c.-765G>C		5_prime_UTR	Exon 1 of 10	NP_001306112.1
RNPEP	NM_001319184.2		c.-619G>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.103G>C	p.Glu35Gln	missense	Exon 1 of 11	ENSP00000295640.4	Q9H4A4
RNPEP	ENST00000967255.1		c.103G>C	p.Glu35Gln	missense	Exon 1 of 11	ENSP00000637314.1
RNPEP	ENST00000857425.1		c.103G>C	p.Glu35Gln	missense	Exon 1 of 11	ENSP00000527484.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1210006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

588756

African (AFR)

AF:

0.00

AC:

AN:

23590

American (AMR)

AF:

0.00

AC:

AN:

9750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16644

East Asian (EAS)

AF:

0.00

AC:

AN:

27088

South Asian (SAS)

AF:

0.00

AC:

AN:

49128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

988220

Other (OTH)

AF:

0.00

AC:

AN:

48802

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.082

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.67

M_CAP

Benign

0.057

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.93

PhyloP100

0.81

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.010

REVEL

Benign

0.021

Sift

Benign

0.71

Sift4G

Benign

0.45

Polyphen

0.0040

Vest4

0.032

MutPred

0.44

Loss of sheet (P = 0.1158)

MVP

0.32

MPC

0.16

ClinPred

0.069

GERP RS

1.9

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.19

gMVP

0.22

Mutation Taster

=87/13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over