rs78599682

Variant names:

• chr12-109561016-T-C
• rs78599682
• NM_052845.4:c.584+24A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052845.4(MMAB):​c.584+24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,118,204 control chromosomes in the GnomAD database, including 4,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (361 hom., cov: 26)
  • Exomes 𝑓: 0.10 (3808 hom.)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.300
• Publications: 4 publications found

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MMAB Gene-Disease associations (from GenCC):

• methylmalonic acidemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• methylmalonic aciduria, cblB type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-109561016-T-C is Benign according to our data. Variant chr12-109561016-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052845.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.584+24A>G		intron	N/A	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.695+24A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.584+24A>G		intron	N/A	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.647+24A>G		intron	N/A	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.584+24A>G		intron	N/A	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 10028 AN: 127884 Hom.: 361 Cov.: 26

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.0511

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.0673

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0927

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0745

Gnomad OTH AF: 0.0912

GnomAD2 exomes AF: 0.0693 AC: 16796 AN: 242440 AF XY: 0.0730

Gnomad AFR exome AF: 0.0678

Gnomad AMR exome AF: 0.0475

Gnomad ASJ exome AF: 0.0848

Gnomad EAS exome AF: 0.0323

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.0702

Gnomad OTH exome AF: 0.0727

GnomAD4 exome AF: 0.101 AC: 99574 AN: 990240 Hom.: 3808 Cov.: 30 AF XY: 0.102 AC XY: 51225 AN XY: 503040

African (AFR) AF: 0.101 AC: 2337 AN: 23132

American (AMR) AF: 0.0570 AC: 2224 AN: 39014

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 2180 AN: 18176

East Asian (EAS) AF: 0.0413 AC: 883 AN: 21374

South Asian (SAS) AF: 0.123 AC: 9779 AN: 79326

European-Finnish (FIN) AF: 0.0848 AC: 2838 AN: 33450

Middle Eastern (MID) AF: 0.129 AC: 563 AN: 4354

European-Non Finnish (NFE) AF: 0.102 AC: 74532 AN: 732068

Other (OTH) AF: 0.108 AC: 4238 AN: 39346

GnomAD4 genome AF: 0.0784 AC: 10033 AN: 127964 Hom.: 361 Cov.: 26 AF XY: 0.0810 AC XY: 4939 AN XY: 60962

African (AFR) AF: 0.0816 AC: 2762 AN: 33832

American (AMR) AF: 0.0804 AC: 940 AN: 11686

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 219 AN: 3252

East Asian (EAS) AF: 0.0362 AC: 140 AN: 3868

South Asian (SAS) AF: 0.132 AC: 487 AN: 3680

European-Finnish (FIN) AF: 0.0927 AC: 647 AN: 6982

Middle Eastern (MID) AF: 0.124 AC: 31 AN: 250

European-Non Finnish (NFE) AF: 0.0745 AC: 4606 AN: 61820

Other (OTH) AF: 0.0902 AC: 158 AN: 1752

Alfa AF: 0.0697 Hom.: 78

Bravo AF: 0.0689

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Methylmalonic aciduria, cblB type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.59
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78599682; hg19: chr12-109998821;