Genetic Variant RNASE11:p.Cys147Tyr (chr14-20584035-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_145250.5(RNASE11):c.440G>A(p.Cys147Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,168 control chromosomes in the GnomAD database, including 5 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 0.000059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 4 hom. )

Consequence

RNASE11
NM_145250.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.289

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014668316).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
RNASE11	NM_001394189.1 link	c.440G>A	p.Cys147Tyr	missense_variant	Exon 3 of 3	NP_001381118.1
RNASE11	NM_001394190.1 link	c.440G>A	p.Cys147Tyr	missense_variant	Exon 3 of 3	NP_001381119.1
RNASE11	NM_001394191.1 link	c.440G>A	p.Cys147Tyr	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.440G>A	p.Cys147Tyr	missense_variant	Exon 3 of 3	3		ENSP00000452412.2		G3V5L6

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251356

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000951

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440G>A (p.C147Y) alteration is located in exon 3 (coding exon 1) of the RNASE11 gene. This alteration results from a G to A substitution at nucleotide position 440, causing the cysteine (C) at amino acid position 147 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

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.11

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.40

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

M_CAP

Benign

0.0074

MetaRNN

Benign

0.015

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

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

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.0

D;D;D;.;D;D;D;D;D

REVEL

Benign

0.14

Sift

Benign

0.19

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

Sift4G

Benign

0.52

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

Polyphen

0.058

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

Vest4

0.074

MVP

0.21

ClinPred

0.025

GERP RS

-3.1

Varity_R

0.12

gMVP

0.23

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