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
• Publications: 13 publications found

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198565.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRROS	NM_198565.3	MANE Select	c.450C>G	p.Ala150Ala	synonymous	Exon 3 of 3	NP_940967.1	Q86YC3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRROS	ENST00000328557.5	TSL:1 MANE Select	c.450C>G	p.Ala150Ala	synonymous	Exon 3 of 3	ENSP00000328625.4	Q86YC3
	NRROS	ENST00000907983.1		c.450C>G	p.Ala150Ala	synonymous	Exon 2 of 2	ENSP00000578042.1
	PIGX	ENST00000426755.5	TSL:3	c.-12+5446C>G		intron	N/A	ENSP00000409073.1	C9JLT7

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

African (AFR) AF: 0.673 AC: 22536 AN: 33470

American (AMR) AF: 0.860 AC: 38447 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22089 AN: 26126

East Asian (EAS) AF: 0.950 AC: 37720 AN: 39692

South Asian (SAS) AF: 0.830 AC: 71597 AN: 86232

European-Finnish (FIN) AF: 0.685 AC: 35829 AN: 52310

Middle Eastern (MID) AF: 0.809 AC: 4667 AN: 5768

European-Non Finnish (NFE) AF: 0.753 AC: 837051 AN: 1111758

Other (OTH) 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

African (AFR) AF: 0.691 AC: 28704 AN: 41526

American (AMR) AF: 0.826 AC: 12619 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 2931 AN: 3468

East Asian (EAS) AF: 0.942 AC: 4878 AN: 5176

South Asian (SAS) AF: 0.839 AC: 4042 AN: 4820

European-Finnish (FIN) AF: 0.672 AC: 7113 AN: 10584

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51565 AN: 67984

Other (OTH) AF: 0.793 AC: 1677 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Seizures, early-onset, with neurodegeneration and brain calcifications (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.9
DANN	Benign	0.77
PhyloP100		-0.21
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

Other links and lift over

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