11-499965-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_203387.3(RNH1):c.307G>A(p.Gly103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,595,648 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

RNH1
NM_203387.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051092505).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNH1	NM_203387.3 link	c.307G>A	p.Gly103Arg	missense_variant	Exon 5 of 11	ENST00000354420.7	NP_976321.1	P13489A0A140VJT8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNH1	ENST00000354420.7 link	c.307G>A	p.Gly103Arg	missense_variant	Exon 5 of 11	5	NM_203387.3	ENSP00000346402.2		P13489

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000354

AC:

AN:

214728

Hom.:

AF XY:

0.000257

AC XY:

AN XY:

116722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.00426

Gnomad EAS exome

AF:

0.0000628

Gnomad SAS exome

AF:

0.0000715

Gnomad FIN exome

AF:

0.0000553

Gnomad NFE exome

AF:

0.000254

Gnomad OTH exome

AF:

0.000555

GnomAD4 exome

AF:

0.000223

AC:

322

AN:

1443316

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

153

AN XY:

716850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00409

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.0000394

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.000453

GnomAD4 genome

AF:

0.000315

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000583

AC:

ExAC

AF:

0.000275

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.307G>A (p.G103R) alteration is located in exon 5 (coding exon 3) of the RNH1 gene. This alteration results from a G to A substitution at nucleotide position 307, causing the glycine (G) at amino acid position 103 to be replaced by an arginine (R). 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

Benign

0.092

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.7

DANN

Benign

0.53

DEOGEN2

Benign

0.053

T;T;T;T;T;T;T;T;T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.59

.;T;.;.;.;.;.;.;T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.0051

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.39

N;N;N;N;N;N;N;N;.;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.86

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.017

Sift

Benign

0.46

T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T;T;T;T;.;T;T;T

Polyphen

0.024

B;B;B;B;B;B;B;B;.;.;.;.

Vest4

0.16

MutPred

0.33

Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);Gain of methylation at G103 (P = 0.0443);

MVP

0.37

MPC

0.17

ClinPred

0.0035

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over