rs35648932

chr12-109561798-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_052845.4(MMAB):c.403G>A(p.Ala135Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000461 in 1,609,506 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A135A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: 6.26

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a chain Corrinoid adenosyltransferase MMAB (size 217) in uniprot entity MMAB_HUMAN there are 32 pathogenic changes around while only 10 benign (76%) in NM_052845.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011106491).
• BP6: Variant 12-109561798-C-T is Benign according to our data. Variant chr12-109561798-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219005.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00248 (377/152296) while in subpopulation AFR AF= 0.00866 (360/41554). AF 95% confidence interval is 0.00793. There are 3 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAB	NM_052845.4	c.403G>A	p.Ala135Thr	missense_variant	5/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.403G>A	p.Ala135Thr	missense_variant	5/9	1	NM_052845.4	P1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000689 AC: 166 AN: 241100 Hom.: 2 AF XY: 0.000489 AC XY: 64 AN XY: 130902

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.000470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1457210 Hom.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 159 AN XY: 724488

Gnomad4 AFR exome AF: 0.00919

Gnomad4 AMR exome AF: 0.000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000515

GnomAD4 genome AF: 0.00248 AC: 377 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74458

Gnomad4 AFR AF: 0.00866

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00308

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000767 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2018	The A135T variant in the MMAB gene has previously been reported in individuals with methylmalonic acidemia (MMA) cblB type who also harbored the R191W pathogenic variant and two of these patients were also reported to be heterozygous for a Y219C variant in MMAB; the phase of these variants was not determined (Dobson et al., 2002; Lerner-Ellis et al., 2006). The A135T variant is observed in 83/6162 (1.4%) alleles from individuals of African background, including 2 homozygous individuals in the ExAC dataset (Lek et al., 2016). The A135T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MMAB: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2022

Variant summary: MMAB c.403G>A (p.Ala135Thr) results in a non-conservative amino acid change located in the cobalamin adenosyltransferase-like domain (IPR016030) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 241100 control chromosomes, predominantly at a frequency of 0.0096 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in MMAB causing Methylmalonic Acidemia phenotype (0.0017), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.403G>A has been reported in the literature in at least two individuals affected with Methylmalonic Acidemia without strong evidence for causality (e.g. Dobson_2002, Lerner-Ellis_2006). These reports do not provide unequivocal conclusions about association of the variant with Methylmalonic Acidemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (Benign n=2, VUS n=1, pathogenic n=1). Based on the evidence outlined above, the variant was classified as benign. -

MMAB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.68
Sift	Benign	0.075	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.94	P;.
Vest4		0.75
MVP		0.98
MPC		0.24
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.49

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: rs35648932; hg19: chr12-109999603; COSMIC: COSV105074843; COSMIC: COSV105074843;