2-240568806-G-C

Variant summary

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

The NM_018226.6(RNPEPL1):c.220G>C(p.Ala74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 946,922 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: 0.0000042 (0 hom.)
• Consequence: RNPEPL1 NM_018226.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.890

Genes affected

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

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]

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=0.27748704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNPEPL1	NM_018226.6	c.220G>C	p.Ala74Pro	missense_variant	1/11	ENST00000270357.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNPEPL1	ENST00000270357.10	c.220G>C	p.Ala74Pro	missense_variant	1/11	1	NM_018226.6	P1
ANKMY1	ENST00000418708.3	c.-122+230C>G		intron_variant		3
RNPEPL1	ENST00000451363.5	c.-57+2865G>C		intron_variant		4
ANKMY1	ENST00000418505.3	n.174+230C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 4 AN: 946922 Hom.: 0 Cov.: 31 AF XY: 0.00000666 AC XY: 3 AN XY: 450660

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: 0.00000480

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 30, 2023

The c.220G>C (p.A74P) alteration is located in exon 1 (coding exon 1) of the RNPEPL1 gene. This alteration results from a G to C substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 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	Uncertain	0.39
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.91
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.28	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
GERP RS		2.1
Varity_R		0.39
gMVP		0.68

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: chr2-241508223;