rs140881518

chr12-109561103-G-A

Variant summary

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

The NM_052845.4(MMAB):c.521C>T(p.Ser174Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000329 in 1,609,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S174S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: MMAB NM_052845.4 missense, splice_region
• Scores: Splicing: ADA: 0.9650
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 7.15

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 Likely_pathogenic. Variant got 6 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-109561103-G-A is Pathogenic according to our data. Variant chr12-109561103-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445684.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAB	NM_052845.4	c.521C>T	p.Ser174Leu	missense_variant, splice_region_variant	7/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.521C>T	p.Ser174Leu	missense_variant, splice_region_variant	7/9	1	NM_052845.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151920 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000644 AC: 16 AN: 248484 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134798

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1457702 Hom.: 0 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 725408

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151920 Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 5 AN XY: 74176

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00000610 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic aciduria, cblB type Pathogenic:3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 07, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Baumgartner lab, University Children's Hospital Zurich	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 05, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 174 of the MMAB protein (p.Ser174Leu). This variant is present in population databases (rs140881518, gnomAD 0.04%). This missense change has been observed in individual(s) with MMAB-related conditions (PMID: 16410054, 23707710, 34796408; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 445684). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.98
MPC		0.74
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.84
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: rs140881518; hg19: chr12-109998908;