Genetic Variant MOCOS:p.Gly17Ser (chr18-36187588-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017947.4(MOCOS):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. G17C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

MOCOS
NM_017947.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.147

Publications

0 publications found

Variant links:

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]

MOCOS links:

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

COSMOC links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05097401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4 link	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4	Q96EN8
COSMOC	NR_134605.1 link	n.-153C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MOCOS	ENST00000261326.6 link	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4	Q96EN8
COSMOC	ENST00000568654.3 link	n.-114C>T		upstream_gene_variant		1
COSMOC	ENST00000687261.3 link	n.-113C>T		upstream_gene_variant
COSMOC	ENST00000738210.1 link	n.-168C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096062

Hom.:

Cov.:

AF XY:

0.00000192

AC XY:

AN XY:

520072

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23456

American (AMR)

AF:

0.00

AC:

AN:

9254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14492

East Asian (EAS)

AF:

0.00

AC:

AN:

27140

South Asian (SAS)

AF:

0.0000446

AC:

AN:

22412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3390

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

928016

Other (OTH)

AF:

0.00

AC:

AN:

44226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.4

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.016

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.34

M_CAP

Benign

0.010

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.15

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.37

REVEL

Benign

0.032

Sift

Benign

0.37

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.14

MutPred

0.15

Gain of phosphorylation at G17 (P = 0.0216);

MVP

0.13

MPC

1.5

ClinPred

0.063

GERP RS

-0.44

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.21

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over