Genetic Variant MMAA:p.Gln133* (chr4-145639536-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_172250.3(MMAA):c.397C>T(p.Gln133*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MMAA
NM_172250.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 7.50

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-145639536-C-T is Pathogenic according to our data. Variant chr4-145639536-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 218973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3 link	c.397C>T	p.Gln133*	stop_gained	Exon 2 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.397C>T	p.Gln133*	stop_gained	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.397C>T	p.Gln133*	stop_gained	Exon 2 of 7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.397C>T	p.Gln133*	stop_gained	Exon 2 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249816

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

44378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110444

Other (OTH)

AF:

0.00

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

PhyloP100

7.5

Vest4

0.95, 0.94

GERP RS

5.4

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over