dbSNP rs35648932: MMAB:p.Ala135Thr (chr12-109561798-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: 6.26

Publications

13 publications found

Variant links:

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]

MMAB Gene-Disease associations (from GenCC):

methylmalonic acidemia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
methylmalonic aciduria, cblB type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Myriad Women’s Health, G2P

MMAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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 VariationId is 219005.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052845.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.403G>A	p.Ala135Thr	missense	Exon 5 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.427G>A		non_coding_transcript_exon	Exon 5 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.403G>A	p.Ala135Thr	missense	Exon 5 of 9	ENSP00000445920.1	Q96EY8
MMAB	ENST00000878519.1		c.466G>A	p.Ala156Thr	missense	Exon 6 of 10	ENSP00000548578.1
MMAB	ENST00000878520.1		c.403G>A	p.Ala135Thr	missense	Exon 5 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152178

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000689

AC:

166

AN:

241100

AF XY:

0.000489

show subpopulations

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 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.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

724488

show subpopulations

African (AFR)

AF:

0.00919

AC:

307

AN:

33396

American (AMR)

AF:

0.000450

AC:

AN:

44408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52668

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109848

Other (OTH)

AF:

0.000515

AC:

AN:

60166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00248

AC:

377

AN:

152296

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00866

AC:

360

AN:

41554

American (AMR)

AF:

0.000915

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00308

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000767

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblB type (3)

not provided (2)

MMAB-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.9

PhyloP100

6.3

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.68

Sift

Benign

0.075

Sift4G

Benign

0.12

Polyphen

0.94

Vest4

0.75

MVP

0.98

MPC

0.24

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.49

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over