1-45500333-A-T

Position:

• chr1-45500333-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001330540.2(MMACHC):​c.-222A>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_001330540.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.22

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 1-45500333-A-T is Pathogenic according to our data. Variant chr1-45500333-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 2725295.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.1A>T	p.Met1?	initiator_codon_variant	1/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.-222A>T		5_prime_UTR_premature_start_codon_gain_variant	1/4		NP_001317469.1
MMACHC	NM_001330540.2	c.-222A>T		5_prime_UTR_variant	1/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.1A>T	p.Met1?	initiator_codon_variant	1/4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.-171A>T		upstream_gene_variant		2		ENSP00000478859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2023

This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 17768669, 19760748, 28693988). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.97	D
PROVEAN	Benign	-1.0	N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.80	P
Vest4		0.97
MutPred		0.99		Loss of methylation at K4 (P = 0.0594);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs758477536; hg19: chr1-45966005;