1-45500333-A-T

Variant names:

• chr1-45500333-A-T
• rs758477536
• NM_015506.3:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 18 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]

CCDC163 (HGNC:27003): (CCDC163 homolog) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 2725295.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330540.2. 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.-222A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001317469.1	A0A0C4DGU2
	MMACHC	NM_001330540.2		c.-222A>T		5_prime_UTR	Exon 1 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000933807.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 3	ENSP00000603866.1
	MMACHC	ENST00000616135.1	TSL:2	c.-171A>T		upstream_gene	N/A	ENSP00000478859.1	A0A0C4DGU2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cobalamin C disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.2
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
PromoterAI		-0.23	Neutral
Varity_R		0.98
gMVP		0.55
Mutation Taster		=3/197	disease causing

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

Other links and lift over

dbSNP: rs758477536; hg19: chr1-45966005;