chr3-196660093-C-G

Variant names:

• chr3-196660093-C-G
• rs1798631
• NM_198565.3:c.450C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198565.3(NRROS):​c.450C>G​(p.Ala150Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,612,578 control chromosomes in the GnomAD database, including 472,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43273 hom., cov: 33)
  • Exomes 𝑓: 0.76 (429084 hom.)
• Consequence: NRROS NM_198565.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.206

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]

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-196660093-C-G is Benign according to our data. Variant chr3-196660093-C-G is described in ClinVar as [Benign]. Clinvar id is 1326993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.206 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRROS	NM_198565.3	c.450C>G	p.Ala150Ala	synonymous_variant	Exon 3 of 3	ENST00000328557.5	NP_940967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRROS	ENST00000328557.5	c.450C>G	p.Ala150Ala	synonymous_variant	Exon 3 of 3	1	NM_198565.3	ENSP00000328625.4
PIGX	ENST00000426755.5	c.-12+5446C>G		intron_variant	Intron 2 of 5	3		ENSP00000409073.1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114349 AN: 152040 Hom.: 43238 Cov.: 33

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.792

GnomAD2 exomes AF: 0.789 AC: 196643 AN: 249246 AF XY: 0.789

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.866

Gnomad ASJ exome AF: 0.844

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.793

GnomAD4 exome AF: 0.765 AC: 1117010 AN: 1460420 Hom.: 429084 Cov.: 62 AF XY: 0.768 AC XY: 557689 AN XY: 726542

Gnomad4 AFR exome AF: 0.673 AC: 22536 AN: 33470

Gnomad4 AMR exome AF: 0.860 AC: 38447 AN: 44686

Gnomad4 ASJ exome AF: 0.845 AC: 22089 AN: 26126

Gnomad4 EAS exome AF: 0.950 AC: 37720 AN: 39692

Gnomad4 SAS exome AF: 0.830 AC: 71597 AN: 86232

Gnomad4 FIN exome AF: 0.685 AC: 35829 AN: 52310

Gnomad4 NFE exome AF: 0.753 AC: 837051 AN: 1111758

Gnomad4 Remaining exome AF: 0.780 AC: 47074 AN: 60378

GnomAD4 genome AF: 0.752 AC: 114444 AN: 152158 Hom.: 43273 Cov.: 33 AF XY: 0.755 AC XY: 56146 AN XY: 74410

Gnomad4 AFR AF: 0.691 AC: 0.69123 AN: 0.69123

Gnomad4 AMR AF: 0.826 AC: 0.825851 AN: 0.825851

Gnomad4 ASJ AF: 0.845 AC: 0.845156 AN: 0.845156

Gnomad4 EAS AF: 0.942 AC: 0.942427 AN: 0.942427

Gnomad4 SAS AF: 0.839 AC: 0.838589 AN: 0.838589

Gnomad4 FIN AF: 0.672 AC: 0.672052 AN: 0.672052

Gnomad4 NFE AF: 0.758 AC: 0.758487 AN: 0.758487

Gnomad4 OTH AF: 0.793 AC: 0.793283 AN: 0.793283

Alfa AF: 0.762 Hom.: 14215

Bravo AF: 0.760

Asia WGS AF: 0.883 AC: 3070 AN: 3478

EpiCase AF: 0.763

EpiControl AF: 0.770

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Seizures, early-onset, with neurodegeneration and brain calcifications Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.9
DANN	Benign	0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1798631; hg19: chr3-196386964; COSMIC: COSV108120305;