rs200483477

Positions:

chr1-45507455-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_015506.3(MMACHC):c.181C>T(p.Arg61Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,614,134 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00099 ( 1 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13O:1

Conservation

PhyloP100: 1.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 49 pathogenic changes around while only 14 benign (78%) in NM_015506.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45507456-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 854802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.077775985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3 linkuse as main transcript	c.181C>T	p.Arg61Trp	missense_variant	2/4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 linkuse as main transcript	c.10C>T	p.Arg4Trp	missense_variant	2/4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 linkuse as main transcript	c.181C>T	p.Arg61Trp	missense_variant	2/4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 linkuse as main transcript	c.10C>T	p.Arg4Trp	missense_variant	2/5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000589

AC:

147

AN:

249498

Hom.:

AF XY:

0.000657

AC XY:

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000987

AC:

1443

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

734

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152260

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.00107

AC:

ExAC

AF:

0.000677

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cobalamin C disease

Uncertain:5Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 61 of the MMACHC protein (p.Arg61Trp). This variant is present in population databases (rs200483477, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 16311595, 19370762). ClinVar contains an entry for this variant (Variation ID: 203824). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	Reported as homozygous in a patient with cobalamin C deficiency who was also homozygous for R111X (PMID: 16311595); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28337550, 19370762, 16311595, 32439973) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2022

The c.181C>T (p.R61W) alteration is located in exon 2 (coding exon 2) of the MMACHC gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Disorders of Intracellular Cobalamin Metabolism

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 22, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

MMACHC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2024

The MMACHC c.181C>T variant is predicted to result in the amino acid substitution p.Arg61Trp. This variant has been reported in multiple individuals with methylmalonic aciduria and homocystinuria (Table 1, Lerner-Ellis et al. 2009. PubMed ID: 19370762). However, this variant has also been observed in cis with another loss-of-function MMACHC variant (p.Arg111*) in multiple individuals (Lerner-Ellis et al. 2005. PubMed ID: 16311595; Internal Data, PreventionGenetics). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Methylmalonic aciduria, type cblc

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 01, 2023

- -

Methylmalonic acidemia with homocystinuria cblC

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 02, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.078

T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-4.3

D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.98

D;.

Vest4

0.38

MVP

0.95

MPC

0.037

ClinPred

0.059

GERP RS

4.4

Varity_R

0.32

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over