rs143912353

Positions:

• chr6-39909873-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS2

The NM_001358530.2(MOCS1):​c.1064T>C​(p.Ile355Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,824 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I355I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: MOCS1 NM_001358530.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 9.17

Genes affected

MOCS1 (HGNC:7190): (molybdenum cofactor synthesis 1) Molybdenum cofactor biosynthesis is a conserved pathway leading to the biological activation of molybdenum. The protein encoded by this gene is involved in this pathway. This gene was originally thought to produce a bicistronic mRNA with the potential to produce two proteins (MOCS1A and MOCS1B) from adjacent open reading frames. However, only the first open reading frame (MOCS1A) has been found to encode a protein from the putative bicistronic mRNA, whereas additional splice variants are likely to produce a fusion between the two open reading frames. This gene is defective in patients with molybdenum cofactor deficiency, type A. A related pseudogene has been identified on chromosome 16. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.07290834).
• BP6: Variant 6-39909873-A-G is Benign according to our data. Variant chr6-39909873-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534543.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCS1	NM_001358530.2	c.1064T>C	p.Ile355Thr	missense_variant	9/11	ENST00000340692.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCS1	ENST00000340692.10	c.1064T>C	p.Ile355Thr	missense_variant	9/11	5	NM_001358530.2	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00149 AC: 374 AN: 251188 Hom.: 1 AF XY: 0.00140 AC XY: 190 AN XY: 135758

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00185 AC: 2705 AN: 1461566 Hom.: 3 Cov.: 32 AF XY: 0.00184 AC XY: 1335 AN XY: 727068

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00171

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74460

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00129

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MOCS1: BS1 -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Uncertain significance and reported on 06-25-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2023	BS1, PP3 -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 12, 2024

Variant summary: MOCS1 c.1064T>C (p.Ile355Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 1613824 control chromosomes in the gnomAD database, including 3 homozygotes. c.1064T>C has been reported in the literature in one individual affected with Molybdenum Cofactor Deficiency (Macaya_2005), as well as in one individual affected with Epilepsy (Gorukmez_2023). These reports do not provide unequivocal conclusions about association of the variant with Sulfite Oxidase Deficiency Due To Molybdenum Cofactor Deficiency Type A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36964972, 36296488, 16429380, 21031595). ClinVar contains an entry for this variant (Variation ID: 534543). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.82
MVP		0.98
ClinPred		0.085	T
GERP RS		5.0
Varity_R		0.93
gMVP		0.87

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

Other links and lift over

dbSNP: rs143912353; hg19: chr6-39877617;