rs201777449

chr1-45507456-G-Achr1-45507456-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PM2 PM5 BP4_Strong

The NM_015506.3(MMACHC):c.182G>A(p.Arg61Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.579

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 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
• PM2: Very rare variant in population databases, with high coverage
• 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=0.061534762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.182G>A	p.Arg61Gln	missense_variant	2/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.11G>A	p.Arg4Gln	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.182G>A	p.Arg61Gln	missense_variant	2/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.11G>A	p.Arg4Gln	missense_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 249474 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 145 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74294

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 12, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 61 of the MMACHC protein (p.Arg61Gln). This variant is present in population databases (rs201777449, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 533860). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. 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	Jan 04, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 14, 2019

ACMG classification criteria: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.043
Dann	Benign	0.87
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.94	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.72	N;.
REVEL	Benign	0.23
Sift	Benign	0.39	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.0010	B;.
Vest4		0.074
MVP		0.48
MPC		0.011
ClinPred		0.012	T
GERP RS		-5.5
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201777449; hg19: chr1-45973128;