rs758477536

chr1-45500333-A-Gchr1-45500333-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_015506.3(MMACHC):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000041 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MMACHC NM_015506.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_015506.3 (MMACHC) was described as [Pathogenic] in ClinVar as 203823
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45500333-A-G is Pathogenic according to our data. Variant chr1-45500333-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 381577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.1A>G	p.Met1?	start_lost	1/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.-222A>G		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.1A>G	p.Met1?	start_lost	1/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249570 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461762 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 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 present in population databases (rs758477536, gnomAD 0.003%). Disruption of the initiator codon has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 17768669, 19760748, 28693988). ClinVar contains an entry for this variant (Variation ID: 381577). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2017

The c.1 A>G pathogenic variant has been reported previously in association with cblC deficiency (Lerner-Ellis et al., 2009; Wang et al., 2012). The c.1 A>G variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met." -

Methylmalonic acidemia with homocystinuria cblC Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.64
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.96
MutPred		1.0		Loss of methylation at K4 (P = 0.105);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.63

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; COSMIC: COSV68984607; COSMIC: COSV68984607;