11-495051-A-C

Position:

• chr11-495051-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_203387.3(RNH1):​c.1130T>G​(p.Leu377Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,451,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNH1 NM_203387.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

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]

RNH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNH1	NM_203387.3	c.1130T>G	p.Leu377Trp	missense_variant, splice_region_variant	10/11	ENST00000354420.7	NP_976321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNH1	ENST00000354420.7	c.1130T>G	p.Leu377Trp	missense_variant, splice_region_variant	10/11	5	NM_203387.3	ENSP00000346402.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451520 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 721302

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Aug 05, 2024

The c.1130T>G (p.L377W) alteration is located in exon 10 (coding exon 8) of the RNH1 gene. This alteration results from a T to G substitution at nucleotide position 1130, causing the leucine (L) at amino acid position 377 to be replaced by a tryptophan (W). 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	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.59	D;D;D;D;T;D;D;D;D
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.66	.;T;.;.;T;.;.;.;.
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	4.0	H;H;H;H;.;H;H;H;H
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D;D;D
Vest4		0.68
MutPred		0.63		Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);.;Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);Gain of catalytic residue at L375 (P = 0.0056);
MVP		0.88
MPC		0.81
ClinPred		0.90	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.64

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: rs1373959021; hg19: chr11-495051;