11-498935-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_203387.3(RNH1):c.615-2A>C variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RNH1 NM_203387.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 3.43

Genes affected

RNH1 (HGNC:10074): (ribonuclease/angiogenin inhibitor 1) Placental ribonuclease inhibitor (PRI) is a member of a family of proteinaceous cytoplasmic RNase inhibitors that occur in many tissues and bind to both intracellular and extracellular RNases (summarized by Lee et al., 1988 [PubMed 3219362]). In addition to control of intracellular RNases, the inhibitor may have a role in the regulation of angiogenin (MIM 105850). Ribonuclease inhibitor, of 50,000 Da, binds to ribonucleases and holds them in a latent form. Since neutral and alkaline ribonucleases probably play a critical role in the turnover of RNA in eukaryotic cells, RNH may be essential for control of mRNA turnover; the interaction of eukaryotic cells with ribonuclease may be reversible in vivo.[supplied by OMIM, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06132756 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNH1	NM_203387.3	c.615-2A>C		splice_acceptor_variant		ENST00000354420.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNH1	ENST00000354420.7	c.615-2A>C		splice_acceptor_variant		5	NM_203387.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Encephalitis, acute, infection-induced, susceptibility to, 12 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 10, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Benign	0.93
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.75	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: -9
DS_AL_spliceai		0.99		Position offset: -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: chr11-498935;