dbSNP rs104893851: MMAA:p.Arg145* (chr4-145639572-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_172250.3(MMAA):c.433C>T(p.Arg145*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000393 in 1,607,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

MMAA
NM_172250.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:2

Conservation

PhyloP100: 4.34

Publications

21 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: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, ClinGen, Ambry Genetics, G2P

MMAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-145639572-C-T is Pathogenic according to our data. Variant chr4-145639572-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172250.3. 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
	MMAA	NM_172250.3	MANE Select	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	NP_758454.1	Q8IVH4
	MMAA	NM_001375644.1		c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	NP_001362573.1	Q8IVH4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMAA	ENST00000649156.2	MANE Select	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENSP00000497008.1	Q8IVH4
MMAA	ENST00000511969.4	TSL:1	n.433C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427422.1	D6RIS5
MMAA	ENST00000541599.5	TSL:5	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENSP00000442284.3	Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000161

AC:

AN:

248412

AF XY:

0.000179

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000416

AC:

606

AN:

1455800

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

290

AN XY:

723200

show subpopulations

African (AFR)

AF:

0.0000904

AC:

AN:

33190

American (AMR)

AF:

0.0000453

AC:

AN:

44138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.000317

AC:

AN:

85234

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000486

AC:

539

AN:

1108490

Other (OTH)

AF:

0.000532

AC:

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000171

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41368

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000341

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblA type (14)

not provided (7)

Methylmalonic acidemia (2)

MMAA-related disorder (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

PhyloP100

4.3

Vest4

0.90

GERP RS

3.0

Mutation Taster

=1/199

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over