rs148579886

Variant names:

• chr6-39909922-G-A
• rs148579886
• NM_001358530.2:c.1015C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_001358530.2(MOCS1):​c.1015C>T​(p.Arg339Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,613,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R339Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (2 hom.)
• Consequence: MOCS1 NM_001358530.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 2.53
• Publications: 6 publications found

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]

MOCS1 Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• BP6: Variant 6-39909922-G-A is Benign according to our data. Variant chr6-39909922-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242559.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358530.2. 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
	MOCS1	NM_001358530.2	MANE Select	c.1015C>T	p.Arg339Trp	missense	Exon 9 of 11	NP_001345459.1	Q9NZB8-1
	MOCS1	NM_001358529.2		c.1015C>T	p.Arg339Trp	missense	Exon 9 of 10	NP_001345458.1	Q9NZB8-2
	MOCS1	NM_001358531.2		c.754C>T	p.Arg252Trp	missense	Exon 8 of 10	NP_001345460.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOCS1	ENST00000340692.10	TSL:5 MANE Select	c.1015C>T	p.Arg339Trp	missense	Exon 9 of 11	ENSP00000344794.5	Q9NZB8-1
	MOCS1	ENST00000373188.6	TSL:1	c.1015C>T	p.Arg339Trp	missense	Exon 9 of 11	ENSP00000362284.2	Q9NZB8-5
	MOCS1	ENST00000373181.8	TSL:1	n.754C>T		non_coding_transcript_exon	Exon 9 of 11	ENSP00000362277.4	Q9NZB8-4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 251044 AF XY: 0.000501

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000714 AC: 1043 AN: 1461414 Hom.: 2 Cov.: 32 AF XY: 0.000697 AC XY: 507 AN XY: 727000

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000649 AC: 29 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86258

European-Finnish (FIN) AF: 0.000189 AC: 10 AN: 52980

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000804 AC: 894 AN: 1111988

Other (OTH) AF: 0.000546 AC: 33 AN: 60392

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74472

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68000

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000586 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000763

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A (3)
-	1	1	not provided (2)
-	1	1	not specified (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	MOCS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		2.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.93
ClinPred		0.85	D
GERP RS		3.1
Varity_R		0.86
gMVP		0.90
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148579886; hg19: chr6-39877666;