NM_015506.3:c.321G>A

Variant names:

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

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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015506.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	NM_015506.3	MANE Select	c.321G>A	p.Val107Val	synonymous	Exon 3 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.150G>A	p.Val50Val	synonymous	Exon 3 of 4	NP_001317469.1	A0A0C4DGU2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	ENST00000401061.9	TSL:2 MANE Select	c.321G>A	p.Val107Val	synonymous	Exon 3 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000616135.1	TSL:2	c.150G>A	p.Val50Val	synonymous	Exon 3 of 5	ENSP00000478859.1	A0A0C4DGU2
	MMACHC	ENST00000933807.1		c.126G>A	p.Val42Val	synonymous	Exon 2 of 3	ENSP00000603866.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Cobalamin C disease (2)
-	-	2	not provided (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

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;