chr4-145639084-A-G

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.-56A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,543,616 control chromosomes in the GnomAD database, including 4,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 386 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4082 hom. )

Consequence

MMAA
NM_172250.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.30

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 4-145639084-A-G is Benign according to our data. Variant chr4-145639084-A-G is described in ClinVar as [Benign]. Clinvar id is 138236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3 link	c.-56A>G	5_prime_UTR_variant	Exon 2 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.-56A>G	5_prime_UTR_variant	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.-56A>G	5_prime_UTR_variant	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.-56A>G		5_prime_UTR_variant	Exon 2 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.0641

AC:

9758

AN:

152188

Hom.:

386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0554

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0490

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.000768

Gnomad SAS

AF:

0.0825

Gnomad FIN

AF:

0.0463

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.0741

Gnomad OTH

AF:

0.0781

GnomAD4 exome

AF:

0.0720

AC:

100137

AN:

1391310

Hom.:

4082

Cov.:

AF XY:

0.0735

AC XY:

51216

AN XY:

696424

show subpopulations

African (AFR)

AF:

0.0559

AC:

1789

AN:

32010

American (AMR)

AF:

0.0402

AC:

1793

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3561

AN:

25684

East Asian (EAS)

AF:

0.000305

AC:

AN:

39344

South Asian (SAS)

AF:

0.101

AC:

8577

AN:

84944

European-Finnish (FIN)

AF:

0.0476

AC:

2529

AN:

53170

Middle Eastern (MID)

AF:

0.167

AC:

945

AN:

5650

European-Non Finnish (NFE)

AF:

0.0730

AC:

76545

AN:

1047952

Other (OTH)

AF:

0.0757

AC:

4386

AN:

57932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

4905

9810

14716

19621

24526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0641

AC:

9766

AN:

152306

Hom.:

386

Cov.:

AF XY:

0.0620

AC XY:

4621

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0556

AC:

2312

AN:

41566

American (AMR)

AF:

0.0490

AC:

749

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

512

AN:

3470

East Asian (EAS)

AF:

0.000770

AC:

AN:

5196

South Asian (SAS)

AF:

0.0827

AC:

399

AN:

4822

European-Finnish (FIN)

AF:

0.0463

AC:

492

AN:

10620

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0741

AC:

5043

AN:

68022

Other (OTH)

AF:

0.0769

AC:

162

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

469

939

1408

1878

2347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0750

Hom.:

786

Bravo

AF:

0.0648

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Benign:2

Jan 12, 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. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 29, 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. -

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

-0.55

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.3

Mutation Taster

=300/0

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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chr4-145639084-A-G

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