rs11721553

chr4-145651075-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_172250.3(MMAA):c.747G>A(p.Ser249=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.51

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]

ACMG classification

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	UniProt
MMAA	NM_172250.3	c.747G>A	p.Ser249=	synonymous_variant	5/7	ENST00000649156.2
MMAA	NM_001375644.1	c.747G>A	p.Ser249=	synonymous_variant	5/7
MMAA	XM_011531684.4	c.747G>A	p.Ser249=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.747G>A	p.Ser249=	synonymous_variant	5/7		NM_172250.3	P1

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11664 AN: 152130 Hom.: 537 Cov.: 32

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

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.: 31 AF XY: 0.0890 AC XY: 64665 AN XY: 726950

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.: 32 AF XY: 0.0714 AC XY: 5311 AN XY: 74434

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Benign:6

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

not specified Benign:4

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

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

Other links and lift over

dbSNP: rs11721553; hg19: chr4-146572227; COSMIC: COSV55580116; COSMIC: COSV55580116;