Genetic Variant RNASE11:p.His132Tyr (chr14-20584081-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145250.5(RNASE11):c.394C>T(p.His132Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RNASE11
NM_145250.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.134

Variant links:

Genes affected

RNASE11 (HGNC:19269): (ribonuclease A family member 11 (inactive)) Predicted to enable endonuclease activity and nucleic acid binding activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

RNASE11 links:

ENSG00000259060 (HGNC:):

ENSG00000259060 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06893358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
RNASE11	NM_001394189.1 link	c.394C>T	p.His132Tyr	missense_variant	Exon 3 of 3	NP_001381118.1
RNASE11	NM_001394190.1 link	c.394C>T	p.His132Tyr	missense_variant	Exon 3 of 3	NP_001381119.1
RNASE11	NM_001394191.1 link	c.394C>T	p.His132Tyr	missense_variant	Exon 3 of 3	NP_001381120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE11	ENST00000557105.6 link	c.394C>T	p.His132Tyr	missense_variant	Exon 3 of 3	3		ENSP00000452412.2		G3V5L6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251306

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727224

show subpopulations

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.394C>T (p.H132Y) alteration is located in exon 3 (coding exon 1) of the RNASE11 gene. This alteration results from a C to T substitution at nucleotide position 394, causing the histidine (H) at amino acid position 132 to be replaced by a tyrosine (Y). 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

0.095

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.46

DANN

Benign

0.90

DEOGEN2

Benign

0.0039

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.33

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

M_CAP

Benign

0.010

MetaRNN

Benign

0.069

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L;L;L;.;.;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

N;N;N;.;N;N;N;N;N;D;D

REVEL

Benign

0.095

Sift

Benign

0.17

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

Sift4G

Benign

0.27

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

Polyphen

0.0010

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

Vest4

0.078

MutPred

0.40

Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);

MVP

0.38

ClinPred

0.018

GERP RS

-1.1

Varity_R

0.046

gMVP

0.35

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.

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