1-201997360-G-A

Position:

• chr1-201997360-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020216.4(RNPEP):​c.896G>A​(p.Gly299Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RNPEP NM_020216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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]

ELF3-AS1 (HGNC:40211): (ELF3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPEP	NM_020216.4	c.896G>A	p.Gly299Glu	missense_variant	5/11	ENST00000295640.9	NP_064601.3
RNPEP	NM_001319182.2	c.503G>A	p.Gly168Glu	missense_variant	5/11		NP_001306111.1
RNPEP	NM_001319183.2	c.26G>A	p.Gly9Glu	missense_variant	4/10		NP_001306112.1
RNPEP	NM_001319184.2	c.26G>A	p.Gly9Glu	missense_variant	4/10		NP_001306113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPEP	ENST00000295640.9	c.896G>A	p.Gly299Glu	missense_variant	5/11	1	NM_020216.4	ENSP00000295640	P1
ELF3-AS1	ENST00000419190.2	n.3632C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.896G>A (p.G299E) alteration is located in exon 5 (coding exon 5) of the RNPEP gene. This alteration results from a G to A substitution at nucleotide position 896, causing the glycine (G) at amino acid position 299 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.70
MutPred		0.85		Gain of disorder (P = 0.1179);.;.;.;
MVP		0.72
MPC		0.76
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.81
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201966488;