rs11721553

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_172250.3(MMAA):c.747G>A(p.Ser249Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,613,392 control chromosomes in the GnomAD database, including 7,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 538 hom., cov: 32)

Exomes 𝑓: 0.091 ( 6705 hom. )

Consequence

MMAA
NM_172250.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.51

Publications

8 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 4-145651075-G-A is Benign according to our data. Variant chr4-145651075-G-A is described in ClinVar as Benign. ClinVar VariationId is 138237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3 link	c.747G>A	p.Ser249Ser	synonymous_variant	Exon 5 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.747G>A	p.Ser249Ser	synonymous_variant	Exon 5 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.747G>A	p.Ser249Ser	synonymous_variant	Exon 5 of 7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.747G>A	p.Ser249Ser	synonymous_variant	Exon 5 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.0767

AC:

11664

AN:

152130

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0610

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0692

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.00731

Gnomad SAS

AF:

0.0377

Gnomad FIN

AF:

0.0325

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0908

GnomAD2 exomes

AF:

0.0707

AC:

17765

AN:

251448

AF XY:

0.0712

show subpopulations

Gnomad AFR exome

AF:

0.0596

Gnomad AMR exome

AF:

0.0515

Gnomad ASJ exome

AF:

0.0664

Gnomad EAS exome

AF:

0.00772

Gnomad FIN exome

AF:

0.0395

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.0800

GnomAD4 exome

AF:

0.0907

AC:

132523

AN:

1461144

Hom.:

6705

Cov.:

AF XY:

0.0890

AC XY:

64665

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.0585

AC:

1960

AN:

33476

American (AMR)

AF:

0.0544

AC:

2431

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0660

AC:

1725

AN:

26132

East Asian (EAS)

AF:

0.00504

AC:

200

AN:

39694

South Asian (SAS)

AF:

0.0358

AC:

3091

AN:

86254

European-Finnish (FIN)

AF:

0.0408

AC:

2180

AN:

53404

Middle Eastern (MID)

AF:

0.0882

AC:

509

AN:

5768

European-Non Finnish (NFE)

AF:

0.103

AC:

115016

AN:

1111326

Other (OTH)

AF:

0.0896

AC:

5411

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

6069

12139

18208

24278

30347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4110

8220

12330

16440

20550

<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:

0.0766

AC:

11668

AN:

152248

Hom.:

538

Cov.:

AF XY:

0.0714

AC XY:

5311

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0608

AC:

2528

AN:

41550

American (AMR)

AF:

0.0691

AC:

1057

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0651

AC:

226

AN:

3470

East Asian (EAS)

AF:

0.00713

AC:

AN:

5186

South Asian (SAS)

AF:

0.0376

AC:

181

AN:

4820

European-Finnish (FIN)

AF:

0.0325

AC:

345

AN:

10602

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6954

AN:

67998

Other (OTH)

AF:

0.0946

AC:

200

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

547

1094

1642

2189

2736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0931

Hom.:

707

Bravo

AF:

0.0804

Asia WGS

AF:

0.0550

AC:

193

AN:

3478

EpiCase

AF:

0.106

EpiControl

AF:

0.109

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Benign:6

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

Oct 03, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.3

(source)

DANN

Benign

0.71

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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