11-498526-A-G

Variant names:

• chr11-498526-A-G
• NM_203387.3:c.887T>C

Variant summary

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

The NM_203387.3(RNH1):​c.887T>C​(p.Leu296Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNH1 NM_203387.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• encephalitis, acute, infection-induced, susceptibility to, 12

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203387.3. 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
	RNH1	NM_203387.3	MANE Select	c.887T>C	p.Leu296Pro	missense	Exon 8 of 11	NP_976321.1	A0A140VJT8
	RNH1	NM_002939.4		c.887T>C	p.Leu296Pro	missense	Exon 8 of 11	NP_002930.2
	RNH1	NM_203383.2		c.887T>C	p.Leu296Pro	missense	Exon 8 of 11	NP_976317.1	P13489

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNH1	ENST00000354420.7	TSL:5 MANE Select	c.887T>C	p.Leu296Pro	missense	Exon 8 of 11	ENSP00000346402.2	P13489
	RNH1	ENST00000356187.9	TSL:1	c.887T>C	p.Leu296Pro	missense	Exon 7 of 10	ENSP00000348515.5	P13489
	RNH1	ENST00000397604.7	TSL:1	c.887T>C	p.Leu296Pro	missense	Exon 7 of 10	ENSP00000380729.3	P13489

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461030 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726820

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Encephalitis, acute, infection-induced, susceptibility to, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.069	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.60		Loss of stability (P = 0.0194)
MVP		0.81
MPC		0.81
ClinPred		0.99	D
GERP RS		3.7
PromoterAI		-0.011	Neutral
Varity_R		0.92
gMVP		0.54
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr11-498526;