Variant 14-20556739-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001110358.1(RNASE9):c.346G>A(p.Glu116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

RNASE9
NM_001110358.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.465

Variant links:

Genes affected

RNASE9 (HGNC:20673): (ribonuclease A family member 9 (inactive)) Predicted to enable nucleic acid binding activity. Predicted to act upstream of or within positive regulation of flagellated sperm motility involved in capacitation. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

RNASE9 links:

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=0.34163472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
RNASE9	NM_001110358.1 link	c.346G>A	p.Glu116Lys	missense_variant	4/4	NP_001103828.1	P60153-2
RNASE9	NM_001110359.1 link	c.346G>A	p.Glu116Lys	missense_variant	5/5	NP_001103829.1	P60153-2
RNASE9	NM_001110360.1 link	c.346G>A	p.Glu116Lys	missense_variant	4/4	NP_001103830.1	P60153-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASE9	ENST00000554964.5 link	c.331G>A	p.Glu111Lys	missense_variant	3/3	1		ENSP00000450599.2		P60153-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152028

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251032

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74250

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

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 submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.346G>A (p.E116K) alteration is located in exon 5 (coding exon 2) of the RNASE9 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the glutamic acid (E) at amino acid position 116 to be replaced by a lysine (K). 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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

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

Eigen

Benign

-0.096

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.64

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

M_CAP

Benign

0.0037

MetaRNN

Benign

0.34

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

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

REVEL

Benign

0.12

Sift

Benign

0.10

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

Sift4G

Uncertain

0.031

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

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;D

Vest4

0.19

MVP

0.60

MPC

0.17

ClinPred

0.31

GERP RS

3.7

Varity_R

0.18

gMVP

0.56

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