Genetic Variant NM_017947.4:c.-5G>A (chr18-36187535-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017947.4(MOCOS):c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,235,088 control chromosomes in the GnomAD database, including 3,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 327 hom., cov: 34)

Exomes 𝑓: 0.076 ( 3316 hom. )

Consequence

MOCOS
NM_017947.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.693

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 18-36187535-G-A is Benign according to our data. Variant chr18-36187535-G-A is described in ClinVar as [Benign]. Clinvar id is 1296803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4 link	c.-5G>A		5_prime_UTR_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4	Q96EN8
COSMOC	NR_134605.1 link	n.-100C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MOCOS	ENST00000261326 link	c.-5G>A	5_prime_UTR_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4	Q96EN8
COSMOC	ENST00000568654.2 link	n.-76C>T	upstream_gene_variant		1
COSMOC	ENST00000687261.2 link	n.-60C>T	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0537

AC:

8176

AN:

152138

Hom.:

327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.0445

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.0695

Gnomad FIN

AF:

0.0578

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0449

GnomAD3 exomes

AF:

0.0761

AC:

673

AN:

8846

Hom.:

AF XY:

0.0761

AC XY:

375

AN XY:

4926

show subpopulations

Gnomad AFR exome

AF:

0.00977

Gnomad AMR exome

AF:

0.0437

Gnomad ASJ exome

AF:

0.0522

Gnomad EAS exome

AF:

0.197

Gnomad SAS exome

AF:

0.0672

Gnomad FIN exome

AF:

0.0429

Gnomad NFE exome

AF:

0.0844

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0758

AC:

82093

AN:

1082838

Hom.:

3316

Cov.:

AF XY:

0.0758

AC XY:

38844

AN XY:

512262

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.0241

Gnomad4 ASJ exome

AF:

0.0434

Gnomad4 EAS exome

AF:

0.141

Gnomad4 SAS exome

AF:

0.0657

Gnomad4 FIN exome

AF:

0.0598

Gnomad4 NFE exome

AF:

0.0777

Gnomad4 OTH exome

AF:

0.0663

GnomAD4 genome

AF:

0.0537

AC:

8173

AN:

152250

Hom.:

327

Cov.:

AF XY:

0.0535

AC XY:

3982

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.0261

Gnomad4 ASJ

AF:

0.0445

Gnomad4 EAS

AF:

0.164

Gnomad4 SAS

AF:

0.0695

Gnomad4 FIN

AF:

0.0578

Gnomad4 NFE

AF:

0.0732

Gnomad4 OTH

AF:

0.0444

Alfa

AF:

0.0304

Hom.:

Bravo

AF:

0.0509

Asia WGS

AF:

0.0760

AC:

264

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MOCOS-related disorder

Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.6

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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