rs2270655

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172250.3(MMAA):c.1089G>C(p.Gln363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,614,116 control chromosomes in the GnomAD database, including 3,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 282 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2884 hom. )

Consequence

MMAA
NM_172250.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.25

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026459396).

BP6

Variant 4-145655266-G-C is Benign according to our data. Variant chr4-145655266-G-C is described in ClinVar as Benign. ClinVar VariationId is 96533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAA	NM_172250.3	MANE Select	c.1089G>C	p.Gln363His	missense	Exon 7 of 7	NP_758454.1
	MMAA	NM_001375644.1		c.1089G>C	p.Gln363His	missense	Exon 7 of 7	NP_001362573.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MMAA	ENST00000649156.2	MANE Select	c.1089G>C	p.Gln363His	missense	Exon 7 of 7	ENSP00000497008.1
MMAA	ENST00000511969.4	TSL:1	n.*220G>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000427422.1
MMAA	ENST00000511969.4	TSL:1	n.*220G>C		3_prime_UTR	Exon 5 of 5	ENSP00000427422.1

Frequencies

GnomAD3 genomes

AF:

0.0527

AC:

8018

AN:

152128

Hom.:

284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.0874

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0545

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0503

Gnomad OTH

AF:

0.0402

GnomAD2 exomes

AF:

0.0643

AC:

16158

AN:

251482

AF XY:

0.0669

show subpopulations

Gnomad AFR exome

AF:

0.0463

Gnomad AMR exome

AF:

0.0623

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0893

Gnomad FIN exome

AF:

0.0595

Gnomad NFE exome

AF:

0.0512

Gnomad OTH exome

AF:

0.0555

GnomAD4 exome

AF:

0.0568

AC:

82974

AN:

1461870

Hom.:

2884

Cov.:

AF XY:

0.0591

AC XY:

42986

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0444

AC:

1488

AN:

33478

American (AMR)

AF:

0.0623

AC:

2785

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0359

AC:

939

AN:

26136

East Asian (EAS)

AF:

0.0911

AC:

3618

AN:

39700

South Asian (SAS)

AF:

0.125

AC:

10788

AN:

86258

European-Finnish (FIN)

AF:

0.0603

AC:

3220

AN:

53418

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5768

European-Non Finnish (NFE)

AF:

0.0511

AC:

56798

AN:

1111994

Other (OTH)

AF:

0.0530

AC:

3203

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4638

9276

13913

18551

23189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2254

4508

6762

9016

11270

<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:

0.0527

AC:

8023

AN:

152246

Hom.:

282

Cov.:

AF XY:

0.0547

AC XY:

4069

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0447

AC:

1858

AN:

41524

American (AMR)

AF:

0.0505

AC:

772

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

140

AN:

3472

East Asian (EAS)

AF:

0.0872

AC:

452

AN:

5184

South Asian (SAS)

AF:

0.147

AC:

708

AN:

4826

European-Finnish (FIN)

AF:

0.0545

AC:

578

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0503

AC:

3420

AN:

68024

Other (OTH)

AF:

0.0397

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

372

744

1116

1488

1860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0501

Hom.:

161

Bravo

AF:

0.0488

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.0458

AC:

202

ESP6500EA

AF:

0.0536

AC:

461

ExAC

AF:

0.0652

AC:

7921

Asia WGS

AF:

0.107

AC:

372

AN:

3478

EpiCase

AF:

0.0456

EpiControl

AF:

0.0456

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblA type (5)

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.17

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.3

PhyloP100

3.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.87

REVEL

Benign

0.24

Sift

Benign

0.43

Sift4G

Benign

0.17

Polyphen

0.0010

Vest4

0.10

MutPred

0.19

Loss of helix (P = 0.1299)

MPC

0.11

ClinPred

0.026

GERP RS

4.8

Varity_R

0.15

gMVP

0.69

Mutation Taster

=59/41

polymorphism (auto)

(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