rs594445

Variant names:

• chr18-36251226-C-A
• rs594445
• NM_017947.4:c.2107C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-36251226-C-A
• chr18-36251226-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017947.4(MOCOS):​c.2107C>A​(p.His703Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,574 control chromosomes in the GnomAD database, including 64,313 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H703D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4804 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59509 hom.)
• Consequence: MOCOS NM_017947.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.58
• Publications: 40 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]

MOCOS Gene-Disease associations (from GenCC):

• xanthinuria type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060777366).
• BP6: Variant 18-36251226-C-A is Benign according to our data. Variant chr18-36251226-C-A is described in ClinVar as Benign. ClinVar VariationId is 1167883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017947.4. 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
	MOCOS	NM_017947.4	MANE Select	c.2107C>A	p.His703Asn	missense	Exon 11 of 15	NP_060417.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOCOS	ENST00000261326.6	TSL:1 MANE Select	c.2107C>A	p.His703Asn	missense	Exon 11 of 15	ENSP00000261326.4
	MOCOS	ENST00000880903.1		c.2107C>A	p.His703Asn	missense	Exon 11 of 16	ENSP00000550962.1
	MOCOS	ENST00000880908.1		c.2017C>A	p.His673Asn	missense	Exon 10 of 14	ENSP00000550967.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35483 AN: 151942 Hom.: 4805 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.276 AC: 69332 AN: 251388 AF XY: 0.278

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.282 AC: 412499 AN: 1461514 Hom.: 59509 Cov.: 36 AF XY: 0.283 AC XY: 205531 AN XY: 727092

African (AFR) AF: 0.0865 AC: 2895 AN: 33474

American (AMR) AF: 0.329 AC: 14723 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 8292 AN: 26134

East Asian (EAS) AF: 0.258 AC: 10232 AN: 39688

South Asian (SAS) AF: 0.273 AC: 23553 AN: 86246

European-Finnish (FIN) AF: 0.306 AC: 16361 AN: 53398

Middle Eastern (MID) AF: 0.303 AC: 1745 AN: 5768

European-Non Finnish (NFE) AF: 0.286 AC: 318048 AN: 1111702

Other (OTH) AF: 0.276 AC: 16650 AN: 60382

GnomAD4 genome AF: 0.233 AC: 35487 AN: 152060 Hom.: 4804 Cov.: 32 AF XY: 0.239 AC XY: 17783 AN XY: 74306

African (AFR) AF: 0.0863 AC: 3582 AN: 41522

American (AMR) AF: 0.319 AC: 4873 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1299 AN: 5172

South Asian (SAS) AF: 0.271 AC: 1304 AN: 4812

European-Finnish (FIN) AF: 0.312 AC: 3288 AN: 10526

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19183 AN: 67972

Other (OTH) AF: 0.274 AC: 579 AN: 2110

Alfa AF: 0.262 Hom.: 19915

Bravo AF: 0.230

TwinsUK AF: 0.284 AC: 1052

ALSPAC AF: 0.293 AC: 1128

ESP6500AA AF: 0.0919 AC: 405

ESP6500EA AF: 0.284 AC: 2442

ExAC AF: 0.269 AC: 32699

Asia WGS AF: 0.236 AC: 826 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.290

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Xanthinuria type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.065
Sift	Benign	0.043	D
Sift4G	Benign	0.093	T
Polyphen		0.084	B
Vest4		0.10
MPC		0.12
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.43
gMVP		0.36
Mutation Taster		=99/1	polymorphism (auto)

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: rs594445; hg19: chr18-33831189; COSMIC: COSV54341969;