2-240568872-G-A

Variant summary

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

The NM_018226.6(RNPEPL1):c.286G>A(p.Ala96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000653 in 1,072,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: RNPEPL1 NM_018226.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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=0.3051425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNPEPL1	NM_018226.6	c.286G>A	p.Ala96Thr	missense_variant	1/11	ENST00000270357.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNPEPL1	ENST00000270357.10	c.286G>A	p.Ala96Thr	missense_variant	1/11	1	NM_018226.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000653 AC: 7 AN: 1072790 Hom.: 0 Cov.: 31 AF XY: 0.00000962 AC XY: 5 AN XY: 519626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000430

Gnomad4 ASJ exome AF: 0.0000729

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000491

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

May 24, 2023

The c.286G>A (p.A96T) alteration is located in exon 1 (coding exon 1) of the RNPEPL1 gene. This alteration results from a G to A substitution at nucleotide position 286, causing the alanine (A) at amino acid position 96 to be replaced by a threonine (T). 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	0.11
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.31	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.4	N
Sift	Uncertain	0.0020	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.050
gMVP		0.27

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: rs932982767; hg19: chr2-241508289;