2-240568935-C-A

Variant names:

• chr2-240568935-C-A
• rs1047115679
• NM_018226.6:c.349C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018226.6(RNPEPL1):​c.349C>A​(p.Pro117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000836 in 1,195,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P117S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: RNPEPL1 NM_018226.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22681409).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018226.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEPL1	NM_018226.6	MANE Select	c.349C>A	p.Pro117Thr	missense	Exon 1 of 11	NP_060696.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEPL1	ENST00000270357.10	TSL:1 MANE Select	c.349C>A	p.Pro117Thr	missense	Exon 1 of 11	ENSP00000270357.4	Q9HAU8
	RNPEPL1	ENST00000971323.1		c.349C>A	p.Pro117Thr	missense	Exon 1 of 11	ENSP00000641382.1
	RNPEPL1	ENST00000971322.1		c.349C>A	p.Pro117Thr	missense	Exon 1 of 11	ENSP00000641381.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1195966 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 585884

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24098

American (AMR) AF: 0.00 AC: 0 AN: 12962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18492

East Asian (EAS) AF: 0.00 AC: 0 AN: 26702

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 985002

Other (OTH) AF: 0.00 AC: 0 AN: 48138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.92
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.23	T
PhyloP100		0.20
PrimateAI	Pathogenic	0.87	D
GERP RS		2.2
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.081
gMVP		0.40
Mutation Taster		=295/5	polymorphism

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

Other links and lift over

dbSNP: rs1047115679; hg19: chr2-241508352;