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GeneBe

11-494958-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

1
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.364
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
RNH1NM_203387.3 linkuse as main transcriptc.1223A>G p.Asn408Ser missense_variant 10/11 ENST00000354420.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNH1ENST00000354420.7 linkuse as main transcriptc.1223A>G p.Asn408Ser missense_variant 10/115 NM_203387.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
34
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 31, 2023The 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

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

Other links and lift over

dbSNP: rs758051830; hg19: chr11-494958; API