1-45508848-G-T

Variant names:

• chr1-45508848-G-T
• rs121918243
• NM_015506.3:c.482G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_015506.3(MMACHC):​c.482G>T​(p.Arg161Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.36
• Publications: 0 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]

MMACHC Gene-Disease associations (from GenCC):

• methylmalonic aciduria and homocystinuria type cblC

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45508847-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 813351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -1.0759 (below the threshold of 3.09). Trascript score misZ: -0.13772 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria and homocystinuria type cblC.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 1-45508848-G-T is Pathogenic according to our data. Variant chr1-45508848-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2013220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.482G>T	p.Arg161Leu	missense_variant	Exon 4 of 4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.311G>T	p.Arg104Leu	missense_variant	Exon 4 of 4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.482G>T	p.Arg161Leu	missense_variant	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.311G>T	p.Arg104Leu	missense_variant	Exon 4 of 5	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cobalamin C disease Pathogenic:1

Jul 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 161 of the MMACHC protein (p.Arg161Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMACHC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg161 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16311595, 17853453, 19370762, 19700356, 20219402, 21055272, 22560872, 25687216, 25809485, 26283149, 28218226). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		9.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.92
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121918243; hg19: chr1-45974520;