NM_015506.3:c.321G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015506.3(MMACHC):c.321G>A(p.Val107Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,613,554 control chromosomes in the GnomAD database, including 161,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 14708 hom., cov: 31)

Exomes 𝑓: 0.45 ( 146400 hom. )

Consequence

MMACHC
NM_015506.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.875

Publications

38 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 1-45508256-G-A is Benign according to our data. Variant chr1-45508256-G-A is described in ClinVar as Benign. ClinVar VariationId is 95702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.875 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.321G>A	p.Val107Val	synonymous_variant	Exon 3 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.150G>A	p.Val50Val	synonymous_variant	Exon 3 of 4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.321G>A	p.Val107Val	synonymous_variant	Exon 3 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 link	c.150G>A	p.Val50Val	synonymous_variant	Exon 3 of 5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66417

AN:

151816

Hom.:

14714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.477

Gnomad EAS

AF:

0.575

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.441

Gnomad OTH

AF:

0.432

GnomAD2 exomes

AF:

0.472

AC:

117763

AN:

249396

AF XY:

0.471

show subpopulations

Gnomad AFR exome

AF:

0.370

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.474

Gnomad EAS exome

AF:

0.579

Gnomad FIN exome

AF:

0.482

Gnomad NFE exome

AF:

0.439

Gnomad OTH exome

AF:

0.461

GnomAD4 exome

AF:

0.446

AC:

652152

AN:

1461620

Hom.:

146400

Cov.:

AF XY:

0.448

AC XY:

325412

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.366

AC:

12266

AN:

33472

American (AMR)

AF:

0.542

AC:

24234

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

12466

AN:

26132

East Asian (EAS)

AF:

0.582

AC:

23086

AN:

39698

South Asian (SAS)

AF:

0.487

AC:

41961

AN:

86248

European-Finnish (FIN)

AF:

0.477

AC:

25484

AN:

53416

Middle Eastern (MID)

AF:

0.455

AC:

2622

AN:

5766

European-Non Finnish (NFE)

AF:

0.434

AC:

482789

AN:

1111784

Other (OTH)

AF:

0.451

AC:

27244

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20879

41758

62636

83515

104394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14794

29588

44382

59176

73970

<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:

0.437

AC:

66409

AN:

151934

Hom.:

14708

Cov.:

AF XY:

0.443

AC XY:

32912

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.376

AC:

15562

AN:

41420

American (AMR)

AF:

0.481

AC:

7341

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

1657

AN:

3472

East Asian (EAS)

AF:

0.574

AC:

2962

AN:

5162

South Asian (SAS)

AF:

0.501

AC:

2409

AN:

4808

European-Finnish (FIN)

AF:

0.481

AC:

5069

AN:

10546

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.441

AC:

29942

AN:

67948

Other (OTH)

AF:

0.427

AC:

902

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1937

3873

5810

7746

9683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<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:

0.442

Hom.:

22283

Bravo

AF:

0.433

Asia WGS

AF:

0.513

AC:

1779

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.451

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Oct 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cobalamin C disease

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 25, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.321G>A in MMACHC gene is a synonymous change that involves a non-conserved nucleotide. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall frequency of 47%, suggesting it is a common polymorphism. The variant has been reported as Benign by several reputable databases/clinical laboratories. Taken together, this variant has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.2

(source)

DANN

Benign

0.68

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism (auto)

(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

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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