11-494958-T-C

Variant summary

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

The NM_203387.3(RNH1):c.1223A>G(p.Asn408Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,607,348 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: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: RNH1 NM_203387.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.364

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35433096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNH1	NM_203387.3	c.1223A>G	p.Asn408Ser	missense_variant	10/11	ENST00000354420.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNH1	ENST00000354420.7	c.1223A>G	p.Asn408Ser	missense_variant	10/11	5	NM_203387.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000682 AC: 16 AN: 234634 Hom.: 0 AF XY: 0.0000549 AC XY: 7 AN XY: 127526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.000723

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.0000513

Gnomad NFE exome AF: 0.0000570

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 101 AN: 1455168 Hom.: 0 Cov.: 37 AF XY: 0.0000691 AC XY: 50 AN XY: 723408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000739

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000495 AC: 6

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 31, 2023

The c.1223A>G (p.N408S) alteration is located in exon 10 (coding exon 8) of the RNH1 gene. This alteration results from a A to G substitution at nucleotide position 1223, causing the asparagine (N) at amino acid position 408 to be replaced by a serine (S). 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	0.41
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.64	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.8	M;M;M;M;.;M;M;M;M
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.073	T;T;T;T;D;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D;D;D
Vest4		0.56
MutPred		0.66		Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);.;Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);Loss of catalytic residue at N408 (P = 0.0297);
MVP		0.91
MPC		0.56
ClinPred		0.61	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
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: rs758051830; hg19: chr11-494958;