rs66580225

Variant names:

• chr12-109571733-A-G
• rs66580225
• NM_052845.4:c.135-23T>C

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.135-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,608,720 control chromosomes in the GnomAD database, including 2,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (280 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2168 hom.)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.895
• Publications: 6 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 aciduria, cblB type

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-109571733-A-G is Benign according to our data. Variant chr12-109571733-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.135-23T>C		intron_variant	Intron 1 of 8	ENST00000545712.7	NP_443077.1
MMAB	NR_038118.2	n.159-23T>C		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.135-23T>C		intron_variant	Intron 1 of 8	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7838 AN: 152082 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0909

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0627

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0455 AC: 11424 AN: 251126 AF XY: 0.0453

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0663

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0479 AC: 69815 AN: 1456520 Hom.: 2168 Cov.: 29 AF XY: 0.0479 AC XY: 34761 AN XY: 724966

African (AFR) AF: 0.0418 AC: 1394 AN: 33370

American (AMR) AF: 0.0264 AC: 1180 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 1715 AN: 26098

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39678

South Asian (SAS) AF: 0.0134 AC: 1151 AN: 86130

European-Finnish (FIN) AF: 0.0878 AC: 4688 AN: 53394

Middle Eastern (MID) AF: 0.0583 AC: 326 AN: 5588

European-Non Finnish (NFE) AF: 0.0511 AC: 56566 AN: 1107396

Other (OTH) AF: 0.0464 AC: 2791 AN: 60166

GnomAD4 genome AF: 0.0516 AC: 7846 AN: 152200 Hom.: 280 Cov.: 32 AF XY: 0.0509 AC XY: 3789 AN XY: 74396

African (AFR) AF: 0.0397 AC: 1651 AN: 41558

American (AMR) AF: 0.0308 AC: 471 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4814

European-Finnish (FIN) AF: 0.0909 AC: 962 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0627 AC: 4267 AN: 68006

Other (OTH) AF: 0.0517 AC: 109 AN: 2110

Alfa AF: 0.0702 Hom.: 114

Bravo AF: 0.0451

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 03, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Methylmalonic aciduria, cblB type Benign:1

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.85
CADD	Benign	7.0
DANN	Benign	0.40
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs66580225; hg19: chr12-110009538; COSMIC: COSV57170409; COSMIC: COSV57170409;