1-201982944-T-C

Position:

• chr1-201982944-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020216.4(RNPEP):​c.278T>C​(p.Leu93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,324 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: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: RNPEP NM_020216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28771466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPEP	NM_020216.4	c.278T>C	p.Leu93Pro	missense_variant	1/11	ENST00000295640.9	NP_064601.3
RNPEP	NM_001319183.2	c.-590T>C		5_prime_UTR_variant	1/10		NP_001306112.1
RNPEP	NM_001319184.2	c.-444T>C		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.278T>C	p.Leu93Pro	missense_variant	1/11	1	NM_020216.4	ENSP00000295640	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333324 Hom.: 0 Cov.: 29 AF XY: 0.00000152 AC XY: 1 AN XY: 656774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000346

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 05, 2024

The c.278T>C (p.L93P) alteration is located in exon 1 (coding exon 1) of the RNPEP gene. This alteration results from a T to C substitution at nucleotide position 278, causing the leucine (L) at amino acid position 93 to be replaced by a proline (P). 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	0.72
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.18
Sift	Benign	0.035	D;T
Sift4G	Benign	0.17	T;T
Polyphen		0.99	D;.
Vest4		0.099
MutPred		0.72		Loss of stability (P = 0.0056);Loss of stability (P = 0.0056);
MVP		0.24
MPC		0.62
ClinPred		0.75	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.79
gMVP		0.82

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: chr1-201952072;