rs6662272

Variant names:

• chr1-45507452-G-A
• rs6662272
• NM_015506.3:c.178G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-45507452-G-A
• chr1-45507452-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_015506.3(MMACHC):​c.178G>A​(p.Asp60Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 6 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, Myriad Women’s Health, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -1.0759 (below the threshold of 3.09). Trascript score misZ: -0.13772 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria and homocystinuria type cblC.

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.178G>A	p.Asp60Asn	missense	Exon 2 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.7G>A	p.Asp3Asn	missense	Exon 2 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.178G>A	p.Asp60Asn	missense	Exon 2 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000616135.1	TSL:2	c.7G>A	p.Asp3Asn	missense	Exon 2 of 5	ENSP00000478859.1	A0A0C4DGU2
	MMACHC	ENST00000933807.1		c.82-760G>A		intron	N/A	ENSP00000603866.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.40		Loss of methylation at K64 (P = 0.1623)
MVP		0.98
MPC		0.057
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.52
gMVP		0.55
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6662272; hg19: chr1-45973124;