rs121908007

Positions:

chr12-56004039-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001032386.2(SUOX):c.650G>A(p.Arg217Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SUOX
NM_001032386.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.90

Variant links:

Genes affected

SUOX (HGNC:11460): (sulfite oxidase) Sulfite oxidase is a homodimeric protein localized to the intermembrane space of mitochondria. Each subunit contains a heme domain and a molybdopterin-binding domain. The enzyme catalyzes the oxidation of sulfite to sulfate, the final reaction in the oxidative degradation of the sulfur amino acids cysteine and methionine. Sulfite oxidase deficiency results in neurological abnormalities which are often fatal at an early age. Alternative splicing results in multiple transcript variants encoding identical proteins. [provided by RefSeq, Jul 2008]

SUOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Moco domain (size 226) in uniprot entity SUOX_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_001032386.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 12-56004039-G-A is Pathogenic according to our data. Variant chr12-56004039-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56004039-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-56004039-G-A is described in Lovd as [Pathogenic]. Variant chr12-56004039-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SUOX	NM_001032386.2 linkuse as main transcript	c.650G>A	p.Arg217Gln	missense_variant	5/5	ENST00000266971.8	NP_001027558.1
SUOX	NM_000456.3 linkuse as main transcript	c.650G>A	p.Arg217Gln	missense_variant	6/6		NP_000447.2
SUOX	NM_001032387.2 linkuse as main transcript	c.650G>A	p.Arg217Gln	missense_variant	4/4		NP_001027559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUOX	ENST00000266971.8 linkuse as main transcript	c.650G>A	p.Arg217Gln	missense_variant	5/5	2	NM_001032386.2	ENSP00000266971	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251490

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000481

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sulfite oxidase deficiency

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 26, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 26, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 217 of the SUOX protein (p.Arg217Gln). This variant is present in population databases (rs121908007, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of sulfite oxidase deficiency (PMID: 9600976, 12368985, 33333793). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R160Q. ClinVar contains an entry for this variant (Variation ID: 3820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SUOX protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SUOX function (PMID: 9600976). This variant disrupts the p.Arg217 amino acid residue in SUOX. Other variant(s) that disrupt this residue have been observed in individuals with SUOX-related conditions (PMID: 28725568), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;D;D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;H;H;H;H

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.96

MVP

0.96

MPC

0.64

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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