rs2275276

Variant names:

• chr1-45508256-G-A
• rs2275276
• NM_015506.3:c.321G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-45508256-G-A
• chr1-45508256-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.875
• Publications: 38 publications found

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

ACMG classification

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	c.321G>A	p.Val107Val	synonymous_variant	Exon 3 of 4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.150G>A	p.Val50Val	synonymous_variant	Exon 3 of 4		NP_001317469.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66417 AN: 151816 Hom.: 14714 Cov.: 31

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

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.: 57 AF XY: 0.448 AC XY: 325412 AN XY: 727140

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

GnomAD4 genome AF: 0.437 AC: 66409 AN: 151934 Hom.: 14708 Cov.: 31 AF XY: 0.443 AC XY: 32912 AN XY: 74246

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

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

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

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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. -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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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. -

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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
DANN	Benign	0.68
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2275276; hg19: chr1-45973928; COSMIC: COSV53113363; COSMIC: COSV53113363;