rs114996305

chr12-109561231-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052845.4(MMAB):c.520-127G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,594,754 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-109561231-C-T is Benign according to our data. Variant chr12-109561231-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00955 (1455/152302) while in subpopulation AFR AF= 0.0333 (1383/41564). AF 95% confidence interval is 0.0318. There are 33 homozygotes in gnomad4. There are 674 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAB	NM_052845.4	c.520-127G>A		intron_variant		ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.520-127G>A		intron_variant		1	NM_052845.4	P1

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1437 AN: 152184 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00262 AC: 593 AN: 226116 Hom.: 15 AF XY: 0.00188 AC XY: 235 AN XY: 124742

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000873

GnomAD4 exome AF: 0.00108 AC: 1563 AN: 1442452 Hom.: 20 Cov.: 33 AF XY: 0.000967 AC XY: 694 AN XY: 717860

Gnomad4 AFR exome AF: 0.0320

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000338

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00256

GnomAD4 genome AF: 0.00955 AC: 1455 AN: 152302 Hom.: 33 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74466

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00560 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.48
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs114996305; hg19: chr12-109999036;