Genetic Variant NM_015506.3:c.1A>T (chr1-45500333-A-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_015506.3(MMACHC):c.1A>T(p.Met1?) variant causes a initiator codon 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_015506.3 initiator_codon

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.22

Publications

18 publications found

Variant links:

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 links:

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

CCDC163 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 58 codons. Genomic position: 45507446. Lost 0.203 part of the original CDS.

PS1

Another start lost variant in NM_015506.3 (MMACHC) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

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_015506.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cobalamin C disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.97

PhyloP100

5.2

PROVEAN

Benign

-1.0

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.80

Vest4

0.97

MutPred

0.99

Loss of methylation at K4 (P = 0.0594)

MVP

0.98

ClinPred

1.0

GERP RS

5.8

PromoterAI

-0.23

Neutral

(source)

Varity_R

0.98

gMVP

0.55

Mutation Taster

=3/197

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over