Variant 3-196660005-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198565.3(NRROS):c.362A>C(p.Tyr121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NRROS
NM_198565.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Variant links:

Genes affected

NRROS (HGNC:24613): (negative regulator of reactive oxygen species) Enables transforming growth factor beta binding activity. Predicted to be involved in several processes, including microglia development; sequestering of TGFbeta in extracellular matrix; and transforming growth factor beta1 activation. Located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

NRROS links:

PIGX (HGNC:26046): (phosphatidylinositol glycan anchor biosynthesis class X) This gene encodes a type I transmembrane protein in the endoplasmic reticulum (ER). The protein is an essential component of glycosylphosphatidylinositol-mannosyltransferase I, which transfers the first of the four mannoses in the GPI-anchor precursors during GPI-anchor biosynthesis. Studies in rat indicate that the protein is translated from a non-AUG translation initiation site. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

PIGX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRROS	NM_198565.3 linkuse as main transcript	c.362A>C	p.Tyr121Ser	missense_variant	3/3	ENST00000328557.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRROS	ENST00000328557.5 linkuse as main transcript	c.362A>C	p.Tyr121Ser	missense_variant	3/3	1	NM_198565.3	P1
PIGX	ENST00000426755.5 linkuse as main transcript	c.-12+5358A>C		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461246

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726960

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.362A>C (p.Y121S) alteration is located in exon 3 (coding exon 2) of the NRROS gene. This alteration results from a A to C substitution at nucleotide position 362, causing the tyrosine (Y) at amino acid position 121 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

Benign

0.14

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

0.017

Eigen_PC

Benign

0.0083

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.57

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.17

Sift

Uncertain

0.012

Sift4G

Benign

0.094

Polyphen

0.81

Vest4

0.64

MutPred

0.50

Gain of disorder (P = 0.0024);

MVP

0.22

MPC

0.62

ClinPred

0.59

GERP RS

3.5

Varity_R

0.30

gMVP

0.66

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