rs752205161

Positions:

• chr1-45508284-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_015506.3(MMACHC):​c.349G>C​(p.Ala117Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.30

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.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• PP5: Variant 1-45508284-G-C is Pathogenic according to our data. Variant chr1-45508284-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552478.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.349G>C	p.Ala117Pro	missense_variant	3/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.178G>C	p.Ala60Pro	missense_variant	3/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.349G>C	p.Ala117Pro	missense_variant	3/4	2	NM_015506.3	ENSP00000383840	P1
MMACHC	ENST00000616135.1	c.178G>C	p.Ala60Pro	missense_variant	3/5	2		ENSP00000478859

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249434 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cobalamin C disease Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2022	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. 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. ClinVar contains an entry for this variant (Variation ID: 552478). This missense change has been observed in individual(s) with MMACHC-related conditions (PMID: 26287336, 29340559). This variant is present in population databases (rs752205161, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 117 of the MMACHC protein (p.Ala117Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.071	T;.
Sift4G	Uncertain	0.053	T;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0479);.;
MVP		0.96
MPC		0.012
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.94

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: rs752205161; hg19: chr1-45973956;