rs76537761

chr12-56004747-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001032386.2(SUOX):c.1358G>A(p.Gly453Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,614,140 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (33 hom.)
• Consequence: SUOX NM_001032386.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.83

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001032386.2
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.026873618).
• BP6: Variant 12-56004747-G-A is Benign according to our data. Variant chr12-56004747-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56004747-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUOX	NM_001032386.2	c.1358G>A	p.Gly453Asp	missense_variant	5/5	ENST00000266971.8
SUOX	NM_000456.3	c.1358G>A	p.Gly453Asp	missense_variant	6/6
SUOX	NM_001032387.2	c.1358G>A	p.Gly453Asp	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUOX	ENST00000266971.8	c.1358G>A	p.Gly453Asp	missense_variant	5/5	2	NM_001032386.2	P1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00379 AC: 953 AN: 251378 Hom.: 4 AF XY: 0.00369 AC XY: 501 AN XY: 135874

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00502 AC: 7345 AN: 1461848 Hom.: 33 Cov.: 34 AF XY: 0.00492 AC XY: 3577 AN XY: 727224

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00587

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00372 AC: 567 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74470

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00566 Hom.: 0

Bravo AF: 0.00378

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00360 AC: 437

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -

Sulfite oxidase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

SUOX-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.78
MVP		0.90
MPC		0.65
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.87
gMVP		0.91

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: rs76537761; hg19: chr12-56398531;