1-45509214-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_015506.3(MMACHC):c.848G>C(p.Ter283Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,932 control chromosomes in the GnomAD database, including 1 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 has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

MMACHC
NM_015506.3 stop_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 1.35

Publications

8 publications found

Variant links:

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MMACHC Gene-Disease associations (from GenCC):

methylmalonic aciduria and homocystinuria type cblC
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

MMACHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Stoplost variant in NM_015506.3 Downstream stopcodon found after 293 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.848G>C	p.Ter283Serext*?	stop_lost	Exon 4 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.677G>C	p.Ter226Serext*?	stop_lost	Exon 4 of 4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMACHC	ENST00000401061.9 link	c.848G>C	p.Ter283Serext*?	stop_lost	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4	Q9Y4U1
MMACHC	ENST00000616135.1 link	c.677G>C	p.Ter226Serext*?	stop_lost	Exon 4 of 5	2		ENSP00000478859.1	A0A0C4DGU2
MMACHC	ENST00000477188.1 link	n.-219G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000258

AC:

AN:

248412

AF XY:

0.000319

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000365

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000235

AC:

344

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000661

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000217

AC:

241

AN:

1112006

Other (OTH)

AF:

0.000282

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000204

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41510

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68002

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000109

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000366

AC:

ExAC

AF:

0.000430

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cobalamin C disease

Uncertain:5

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change disrupts the translational stop signal of the MMACHC mRNA. It is expected to extend the length of the MMACHC protein by 14 additional amino acid residues. This variant is present in population databases (rs201025783, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This protein extension has been observed in individual(s) with clinical features of cobalamin C deficiency (PMID: 31130284). ClinVar contains an entry for this variant (Variation ID: 554073). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 26, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Oct 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM4 -

Jan 25, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 10, 2018

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MMACHC c.848G>C (p.X283SerextX14) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 0.00026 in 276092 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (0.00026 vs 0.0031), allowing no conclusion about variant significance. Another variant affecting the same nucleotide and leading to a different, though functionally similar protein level change, MMACHC c.848G>T (p.Ter283LeuextTer14) is reported in 275/276092 gnomAD alleles, almost exclusively observed within the Latino subpopulation with 274/34392 alleles (frequency: 0.008), including 4 homozygotes. This frequency is higher than the MPAF (0.0031), suggesting that the loss of STOP codon leading to a 14 amino acid extension of the protein might not be detrimental for protein function. c.848G>C has been reported in the literature (Abuli 2016). This report however does not provide unequivocal conclusions about association of the variant with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Methylmalonic acidemia with homocystinuria cblC

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.74

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.83

PhyloP100

1.4

Vest4

0.082

GERP RS

3.5

Mutation Taster

=57/143

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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