4-145639084-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30

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 -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	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.-56A>G		5_prime_UTR_variant	2/7	ENST00000649156.2
MMAA	NM_001375644.1	c.-56A>G		5_prime_UTR_variant	2/7
MMAA	XM_011531684.4	c.-56A>G		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.-56A>G		5_prime_UTR_variant	2/7		NM_172250.3	P1

Frequencies

GnomAD3 genomes AF: 0.0641 AC: 9758 AN: 152188 Hom.: 386 Cov.: 32

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.: 24 AF XY: 0.0735 AC XY: 51216 AN XY: 696424

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.000305

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0730

Gnomad4 OTH exome AF: 0.0757

GnomAD4 genome AF: 0.0641 AC: 9766 AN: 152306 Hom.: 386 Cov.: 32 AF XY: 0.0620 AC XY: 4621 AN XY: 74482

Gnomad4 AFR AF: 0.0556

Gnomad4 AMR AF: 0.0490

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0827

Gnomad4 FIN AF: 0.0463

Gnomad4 NFE AF: 0.0741

Gnomad4 OTH AF: 0.0769

Alfa AF: 0.0755 Hom.: 634

Bravo AF: 0.0648

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.92

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

LitVar

Other links and lift over

dbSNP: rs4835011; hg19: chr4-146560236; COSMIC: COSV55579714; COSMIC: COSV55579714;