rs765913293

Positions:

• chr1-45508982-CG-C
• chr1-45508982-CG-CGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_015506.3(MMACHC):​c.619del​(p.Asp207MetfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). 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 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.37

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45508982-CG-C is Pathogenic according to our data. Variant chr1-45508982-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1453735.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.619del	p.Asp207MetfsTer3	frameshift_variant	4/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.448del	p.Asp150MetfsTer3	frameshift_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.619del	p.Asp207MetfsTer3	frameshift_variant	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.448del	p.Asp150MetfsTer3	frameshift_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cobalamin C disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2020

This sequence change creates a premature translational stop signal (p.Asp207Metfs*3) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the MMACHC protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MMACHC protein. Other variant(s) that disrupt this region (p.Tyr222*) have been determined to be pathogenic (PMID: 16311595, 19767224, 30157807). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with MMACHC-related conditions. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45974654;