12-56003721-T-C

Variant names:

• chr12-56003721-T-C
• rs794729211
• NM_001032386.2:c.332T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001032386.2(SUOX):​c.332T>C​(p.Val111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V111D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SUOX NM_001032386.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• isolated sulfite oxidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-56003721-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 202185.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032386.2. 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
	SUOX	NM_001032386.2	MANE Select	c.332T>C	p.Val111Ala	missense	Exon 5 of 5	NP_001027558.1	P51687
	SUOX	NM_000456.3		c.332T>C	p.Val111Ala	missense	Exon 6 of 6	NP_000447.2	P51687
	SUOX	NM_001032387.2		c.332T>C	p.Val111Ala	missense	Exon 4 of 4	NP_001027559.1	P51687

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUOX	ENST00000266971.8	TSL:2 MANE Select	c.332T>C	p.Val111Ala	missense	Exon 5 of 5	ENSP00000266971.3	P51687
	SUOX	ENST00000356124.8	TSL:1	c.332T>C	p.Val111Ala	missense	Exon 4 of 4	ENSP00000348440.4	P51687
	SUOX	ENST00000394109.7	TSL:1	c.332T>C	p.Val111Ala	missense	Exon 3 of 3	ENSP00000377668.3	P51687

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.31
MutPred		0.60		Loss of helix (P = 0.0558)
MVP		0.82
MPC		0.40
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.89
Mutation Taster		=43/57	disease causing

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: rs794729211; hg19: chr12-56397505;