1-45500344-AGTCGCAGAGCT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015506.3(MMACHC):c.14_24del(p.Val5GlufsTer25) variant causes a frameshift change. 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. V5V) 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: 5.57

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 108 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45500344-AGTCGCAGAGCT-A is Pathogenic according to our data. Variant chr1-45500344-AGTCGCAGAGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2202756.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.14_24del	p.Val5GlufsTer25	frameshift_variant	1/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.-209_-199del		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.14_24del	p.Val5GlufsTer25	frameshift_variant	1/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.-158_-148del		5_prime_UTR_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

May 28, 2022

This sequence change creates a premature translational stop signal (p.Val5Glufs*25) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 19370762, 23837176). -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr1-45966016;