6-39912909-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001358530.2(MOCS1):c.853G>A(p.Glu285Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000994 in 1,614,142 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. E285Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

MOCS1
NM_001358530.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 1.02

Publications

4 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen

MOCS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013013929).

BP6

Variant 6-39912909-C-T is Benign according to our data. Variant chr6-39912909-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242558.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000867 (132/152292) while in subpopulation AMR AF = 0.00255 (39/15304). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCS1	NM_001358530.2 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 7 of 11	ENST00000340692.10	NP_001345459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCS1	ENST00000340692.10 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 7 of 11	5	NM_001358530.2	ENSP00000344794.5		Q9NZB8-1

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000767

AC:

193

AN:

251492

AF XY:

0.000846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00101

AC:

1473

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

739

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000719

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00116

AC:

1287

AN:

1111978

Other (OTH)

AF:

0.000844

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000867

AC:

132

AN:

152292

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41564

American (AMR)

AF:

0.00255

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68020

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000675

AC:

EpiCase

AF:

0.00180

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

Uncertain:3Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.853G>A (p.E285K) alteration is located in exon 6 (coding exon 6) of the MOCS1 gene. This alteration results from a G to A substitution at nucleotide position 853, causing the glutamic acid (E) at amino acid position 285 to be replaced by a lysine (K). The p.E285K alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MOCS1 p.Glu285Lys variant was identified in 1 of 52 proband chromosomes (frequency: 0.019) from individuals with a known or suspected mitochondrial disorder, however the variant was suggested to be benign (Vasta_2012_PMID:22494076). The variant was identified in dbSNP (ID: rs140243105), ClinVar (classified as uncertain significance by Illumina, Fulgent Genetics, CeGaT Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences; classified as likely benign by Mendelics when found in combination with the p.E285K variant) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 210 of 282890 chromosomes (3 homozygous) at a frequency of 0.0007423 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 8 of 7226 chromosomes (freq: 0.001107), European (non-Finnish) in 138 of 129192 chromosomes (freq: 0.001068), Latino in 37 of 35440 chromosomes (freq: 0.001044), South Asian in 20 of 30616 chromosomes (freq: 0.000653), Ashkenazi Jewish in 4 of 10370 chromosomes (freq: 0.000386), African in 2 of 24968 chromosomes (freq: 0.00008), European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Glu285 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

MOCS1-related disorder

Benign:1

Oct 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MOCS1: BP4, BS2 -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.30

.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.16

N;.;N

PhyloP100

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.88

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.60

T;T;T

Sift4G

Benign

0.59

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.26

MVP

0.66

ClinPred

0.023

GERP RS

4.0

Varity_R

0.084

gMVP

0.51

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over