chr1-201983100-G-A

Position:

• chr1-201983100-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020216.4(RNPEP):​c.434G>A​(p.Gly145Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000816 in 1,348,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RNPEP NM_020216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2575035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPEP	NM_020216.4	c.434G>A	p.Gly145Glu	missense_variant	1/11	ENST00000295640.9	NP_064601.3
RNPEP	NM_001319183.2	c.-434G>A		5_prime_UTR_variant	1/10		NP_001306112.1
RNPEP	NM_001319184.2	c.-288G>A		5_prime_UTR_variant	1/10		NP_001306113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPEP	ENST00000295640.9	c.434G>A	p.Gly145Glu	missense_variant	1/11	1	NM_020216.4	ENSP00000295640	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000816 AC: 11 AN: 1348064 Hom.: 0 Cov.: 29 AF XY: 0.00000451 AC XY: 3 AN XY: 665196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000938

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000340

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

Aug 26, 2022

The c.434G>A (p.G145E) alteration is located in exon 1 (coding exon 1) of the RNPEP gene. This alteration results from a G to A substitution at nucleotide position 434, causing the glycine (G) at amino acid position 145 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	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.10
Sift	Benign	0.13	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.86	P;.
Vest4		0.32
MutPred		0.53		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.43
MPC		0.49
ClinPred		0.81	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.12
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1376183425; hg19: chr1-201952228;