Genetic Variant RNPEPL1:p.Glu64Gln (chr2-240568776-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018226.6(RNPEPL1):c.190G>C(p.Glu64Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000465 in 1,075,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

RNPEPL1
NM_018226.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

Publications

0 publications found

Variant links:

Genes affected

RNPEPL1 (HGNC:10079): (arginyl aminopeptidase like 1) Enables metalloaminopeptidase activity. Involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

RNPEPL1 links:

ANKMY1 (HGNC:20987): (ankyrin repeat and MYND domain containing 1) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ANKMY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018226.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEPL1	NM_018226.6	MANE Select	c.190G>C	p.Glu64Gln	missense	Exon 1 of 11	NP_060696.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNPEPL1	ENST00000270357.10	TSL:1 MANE Select	c.190G>C	p.Glu64Gln	missense	Exon 1 of 11	ENSP00000270357.4	Q9HAU8
RNPEPL1	ENST00000971323.1		c.190G>C	p.Glu64Gln	missense	Exon 1 of 11	ENSP00000641382.1
RNPEPL1	ENST00000971322.1		c.190G>C	p.Glu64Gln	missense	Exon 1 of 11	ENSP00000641381.1

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

146464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000303

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

4532

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000323

AC:

AN:

928726

Hom.:

Cov.:

AF XY:

0.00000455

AC XY:

AN XY:

439742

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

17534

American (AMR)

AF:

0.00

AC:

AN:

3732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7654

East Asian (EAS)

AF:

0.00

AC:

AN:

9956

South Asian (SAS)

AF:

0.00

AC:

AN:

25166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2042

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

821254

Other (OTH)

AF:

0.00

AC:

AN:

32242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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:

0.0000137

AC:

AN:

146464

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40654

American (AMR)

AF:

0.00

AC:

AN:

14778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00

AC:

AN:

5022

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.0000303

AC:

AN:

65922

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000132

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

Uncertain

0.36

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.91

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.54

MetaRNN

Uncertain

0.47

PhyloP100

3.3

PrimateAI

Pathogenic

0.89

GERP RS

1.1

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.084

gMVP

0.34

Mutation Taster

=300/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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