rs11721553

Positions:

chr4-145651075-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 links:

MMAA (HGNC:):

MMAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 138237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-145651075-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MMAA	NM_172250.3 linkuse as main transcript	c.747G>A	p.Ser249Ser	synonymous_variant	5/7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 linkuse as main transcript	c.747G>A	p.Ser249Ser	synonymous_variant	5/7		NP_001362573.1
MMAA	XM_011531684.4 linkuse as main transcript	c.747G>A	p.Ser249Ser	synonymous_variant	5/7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 linkuse as main transcript	c.747G>A	p.Ser249Ser	synonymous_variant	5/7		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

GnomAD3 exomes

AF:

0.0707

AC:

17765

AN:

251448

Hom.:

810

AF XY:

0.0712

AC XY:

9672

AN XY:

135898

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 SAS exome

AF:

0.0377

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

Gnomad4 AFR exome

AF:

0.0585

Gnomad4 AMR exome

AF:

0.0544

Gnomad4 ASJ exome

AF:

0.0660

Gnomad4 EAS exome

AF:

0.00504

Gnomad4 SAS exome

AF:

0.0358

Gnomad4 FIN exome

AF:

0.0408

Gnomad4 NFE exome

AF:

0.103

Gnomad4 OTH exome

AF:

0.0896

GnomAD4 genome

AF:

0.0766

AC:

11668

AN:

152248

Hom.:

538

Cov.:

AF XY:

0.0714

AC XY:

5311

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0608

Gnomad4 AMR

AF:

0.0691

Gnomad4 ASJ

AF:

0.0651

Gnomad4 EAS

AF:

0.00713

Gnomad4 SAS

AF:

0.0376

Gnomad4 FIN

AF:

0.0325

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.0946

Alfa

AF:

0.0954

Hom.:

470

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

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.3

DANN

Benign

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over