rs1682981215

Variant names:

• chr1-201982769-G-A
• rs1682981215
• NM_020216.4:c.103G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-201982769-G-A
• chr1-201982769-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020216.4(RNPEP):​c.103G>A​(p.Glu35Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,361,750 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: RNPEP NM_020216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.808
• Publications: 0 publications found

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]

ACMG classification

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=0.055530608).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEP	NM_020216.4	MANE Select	c.103G>A	p.Glu35Lys	missense	Exon 1 of 11	NP_064601.3
	RNPEP	NM_001319183.2		c.-765G>A		5_prime_UTR	Exon 1 of 10	NP_001306112.1
	RNPEP	NM_001319184.2		c.-619G>A		5_prime_UTR	Exon 1 of 10	NP_001306113.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEP	ENST00000295640.9	TSL:1 MANE Select	c.103G>A	p.Glu35Lys	missense	Exon 1 of 11	ENSP00000295640.4	Q9H4A4
	RNPEP	ENST00000967255.1		c.103G>A	p.Glu35Lys	missense	Exon 1 of 11	ENSP00000637314.1
	RNPEP	ENST00000857425.1		c.103G>A	p.Glu35Lys	missense	Exon 1 of 11	ENSP00000527484.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151744 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1210006 Hom.: 0 Cov.: 29 AF XY: 0.00000340 AC XY: 2 AN XY: 588756

African (AFR) AF: 0.00 AC: 0 AN: 23590

American (AMR) AF: 0.000103 AC: 1 AN: 9750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16644

East Asian (EAS) AF: 0.00 AC: 0 AN: 27088

South Asian (SAS) AF: 0.00 AC: 0 AN: 49128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4670

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 988220

Other (OTH) AF: 0.0000205 AC: 1 AN: 48802

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151744 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74120

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

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.0000657 AC: 1 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.81
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.67	N
REVEL	Benign	0.051
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.57		Gain of methylation at E35 (P = 0.0175)
MVP		0.20
MPC		0.18
ClinPred		0.11	T
GERP RS		1.9
PromoterAI		-0.019	Neutral
Varity_R		0.21
gMVP		0.25
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1682981215; hg19: chr1-201951897;