rs72650187

Positions:

• chr12-109561869-A-G

Variant summary

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

The ENST00000545712.7(MMAB):​c.349-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00808 in 1,593,234 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (66 hom.)
• Consequence: MMAB ENST00000545712.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.557

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=-0.88).
• BP6: Variant 12-109561869-A-G is Benign according to our data. Variant chr12-109561869-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109561869-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00561 (855/152298) while in subpopulation NFE AF= 0.00972 (661/68018). AF 95% confidence interval is 0.0091. There are 2 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAB	NM_052845.4	c.349-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.349-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_052845.4	ENSP00000445920	P1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 856 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00649

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00972

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00579 AC: 1240 AN: 214260 Hom.: 10 AF XY: 0.00599 AC XY: 693 AN XY: 115714

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000746

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00390

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00834 AC: 12017 AN: 1440936 Hom.: 66 Cov.: 32 AF XY: 0.00819 AC XY: 5854 AN XY: 715020

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.000777

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.00965

Gnomad4 NFE exome AF: 0.00971

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00561 AC: 855 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74478

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00649

Gnomad4 NFE AF: 0.00972

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00731 Hom.: 2

Bravo AF: 0.00496

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 03, 2017	- -

Methylmalonic aciduria, cblB type Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2017

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	-0.88
CADD	Benign	11
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72650187; hg19: chr12-109999674;