rs2275276

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015506.3(MMACHC):c.321G>A(p.Val107=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. VHPN107VH?) has been classified as Pathogenic.

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:10

Conservation

PhyloP100: -0.875

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45508256-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
MMACHC	NM_015506.3 linkuse as main transcript	c.321G>A	p.Val107=	synonymous_variant	3/4	ENST00000401061.9
MMACHC	NM_001330540.2 linkuse as main transcript	c.150G>A	p.Val50=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9 linkuse as main transcript	c.321G>A	p.Val107=	synonymous_variant	3/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1 linkuse as main transcript	c.150G>A	p.Val50=	synonymous_variant	3/5	2

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

GnomAD3 exomes

AF:

0.472

AC:

117763

AN:

249396

Hom.:

28151

AF XY:

0.471

AC XY:

63786

AN XY:

135322

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 SAS exome

AF:

0.486

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

Gnomad4 AFR exome

AF:

0.366

Gnomad4 AMR exome

AF:

0.542

Gnomad4 ASJ exome

AF:

0.477

Gnomad4 EAS exome

AF:

0.582

Gnomad4 SAS exome

AF:

0.487

Gnomad4 FIN exome

AF:

0.477

Gnomad4 NFE exome

AF:

0.434

Gnomad4 OTH exome

AF:

0.451

GnomAD4 genome

AF:

0.437

AC:

66409

AN:

151934

Hom.:

14708

Cov.:

AF XY:

0.443

AC XY:

32912

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.376

Gnomad4 AMR

AF:

0.481

Gnomad4 ASJ

AF:

0.477

Gnomad4 EAS

AF:

0.574

Gnomad4 SAS

AF:

0.501

Gnomad4 FIN

AF:

0.481

Gnomad4 NFE

AF:

0.441

Gnomad4 OTH

AF:

0.427

Alfa

AF:

0.443

Hom.:

19892

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cobalamin C disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 25, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

Cadd

Benign

2.2

Dann

Benign

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over