rs761964238

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_172250.3(MMAA):c.833G>A(p.Gly278Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G278S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MMAA
NM_172250.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 9.56

Publications

3 publications found

Variant links:

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMAA Gene-Disease associations (from GenCC):

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

MMAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-145654006-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1985168.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 4-145654007-G-A is Pathogenic according to our data. Variant chr4-145654007-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552542.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MMAA	NM_172250.3 link	c.833G>A	p.Gly278Asp	missense_variant	Exon 6 of 7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1 link	c.833G>A	p.Gly278Asp	missense_variant	Exon 6 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.833G>A	p.Gly278Asp	missense_variant	Exon 6 of 7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.833G>A	p.Gly278Asp	missense_variant	Exon 6 of 7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251456

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:2Uncertain:2

Jan 12, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 278 of the MMAA protein (p.Gly278Asp). This variant is present in population databases (rs761964238, gnomAD 0.003%). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin A type (PMID: 23716945; 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: 552542). 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) performed at Invitae indicates that this missense variant is expected to disrupt MMAA protein function. For these reasons, this variant has been classified as Pathogenic. -

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

MMAA-related disorder

Pathogenic:1

Jan 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MMAA c.833G>A variant is predicted to result in the amino acid substitution p.Gly278Asp. This variant was reported in the homozygous state in two individuals with methylmalonic acidemia, cblA type (Girisha et al. 2012. PubMed ID: 23716945; Şeker Yılmaz et al. 2021. PubMed ID: 33453710) and functional studies support pathogenicity of the p.Gly278Asp substitution (Ruetz et al. 2019. PubMed ID: 31056463). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146575159-G-A). Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D;D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;.;.;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;H;H;H;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.5

.;.;D;.;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;.;D;.;.;.

Sift4G

Uncertain

0.0020

.;.;D;.;.;D

Polyphen

1.0

D;.;D;D;D;.

Vest4

0.99, 0.99

MutPred

0.93

Gain of relative solvent accessibility (P = 0.09);.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);

MVP

0.91

MPC

0.63

ClinPred

1.0

GERP RS

5.8

Varity_R

0.98

gMVP

0.96

Mutation Taster

=156/144

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over