18-36187543-G-T

Variant names:

• chr18-36187543-G-T
• rs1026277944
• NM_017947.4:c.4G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017947.4(MOCOS):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. A2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MOCOS NM_017947.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.730
• Publications: 0 publications found

Genes affected

MOCOS (HGNC:18234): (molybdenum cofactor sulfurase) This gene encodes an enzyme that sulfurates the molybdenum cofactor which is required for activation of the xanthine dehydrogenase (XDH) and aldehyde oxidase (AO) enzymes. XDH catalyzes the conversion of hypoxanthine to uric acid via xanthine, as well as the conversion of allopurinol to oxypurinol, and pyrazinamide to 5-hydroxy pyrazinamide. Mutations in this gene cause the metabolic disorder classical xanthinuria type II which is characterized by the loss of XDH/XO and AO enzyme activity, decreased levels of uric acid in the urine, increased levels of xanthine and hypoxanthine in the serum and urine, formation of xanthine stones in the urinary tract, and myositis due to tissue deposition of xanthine. [provided by RefSeq, Apr 2017]

COSMOC (HGNC:51610): (cell fate and sterol metabolism associated divergent transcript of MOCOS)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32946467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4
COSMOC	NR_134605.1	n.-108C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCOS	ENST00000261326.6	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4
COSMOC	ENST00000568654.3	n.-69C>A		upstream_gene_variant		1
COSMOC	ENST00000687261.3	n.-68C>A		upstream_gene_variant
COSMOC	ENST00000738210.1	n.-123C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1084788 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 513434

African (AFR) AF: 0.00 AC: 0 AN: 23040

American (AMR) AF: 0.00 AC: 0 AN: 8704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14304

East Asian (EAS) AF: 0.00 AC: 0 AN: 26686

South Asian (SAS) AF: 0.00 AC: 0 AN: 20444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3008

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 922144

Other (OTH) AF: 0.00 AC: 0 AN: 43768

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.73
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.18
MutPred		0.18		Gain of glycosylation at A2 (P = 0.0028);
MVP		0.45
MPC		1.4
ClinPred		0.71	D
GERP RS		4.1
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.35

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: rs1026277944; hg19: chr18-33767506;