rs114996305

Variant names:

• chr12-109561231-C-T
• rs114996305
• NM_052845.4:c.520-127G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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 12-109561231-C-T is Benign according to our data. Variant chr12-109561231-C-T is described in ClinVar as Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

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.520-127G>A		intron	N/A	NP_443077.1
	MMAB	NR_038118.2		n.630+12G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.520-127G>A		intron	N/A	ENSP00000445920.1
	MMAB	ENST00000878519.1		c.583-127G>A		intron	N/A	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.520-127G>A		intron	N/A	ENSP00000548579.1

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

GnomAD2 exomes AF: 0.00262 AC: 593 AN: 226116 AF XY: 0.00188

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 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

African (AFR) AF: 0.0320 AC: 1068 AN: 33372

American (AMR) AF: 0.00194 AC: 86 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39514

South Asian (SAS) AF: 0.000338 AC: 29 AN: 85694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38008

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.000192 AC: 213 AN: 1109662

Other (OTH) AF: 0.00256 AC: 154 AN: 60084

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

African (AFR) AF: 0.0333 AC: 1383 AN: 41564

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00612 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.48
DANN	Benign	0.80
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs114996305; hg19: chr12-109999036;