1-45508984-G-C

Variant names:

• chr1-45508984-G-C
• NM_015506.3:c.618G>C
• MMACHC p.Arg206Arg

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_015506.3(MMACHC):​c.618G>C​(p.Arg206Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R206R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_015506.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.601
• Publications: 0 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women's Health, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=0.601 with no splicing effect.

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.618G>C	p.Arg206Arg	synonymous	Exon 4 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.447G>C	p.Arg149Arg	synonymous	Exon 4 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.618G>C	p.Arg206Arg	synonymous	Exon 4 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000616135.1	TSL:2	c.447G>C	p.Arg149Arg	synonymous	Exon 4 of 5	ENSP00000478859.1	A0A0C4DGU2
	MMACHC	ENST00000933807.1		c.423G>C	p.Arg141Arg	synonymous	Exon 3 of 3	ENSP00000603866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.2
DANN	Benign	0.71
PhyloP100		0.60
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-45974656;