chr12-109556171-C-G

Variant names:

• chr12-109556171-C-G
• rs877710
• NM_052845.4:c.*857G>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.*857G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 453,090 control chromosomes in the GnomAD database, including 65,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25473 hom., cov: 31)
  • Exomes 𝑓: 0.51 (39558 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.277
• Publications: 25 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=-0.86).
• BP6: Variant 12-109556171-C-G is Benign according to our data. Variant chr12-109556171-C-G is described in ClinVar as Benign. ClinVar VariationId is 307047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 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.*857G>C		3_prime_UTR	Exon 9 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.1721G>C		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.*857G>C		3_prime_UTR	Exon 9 of 9	ENSP00000445920.1	Q96EY8

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86129 AN: 151894 Hom.: 25429 Cov.: 31

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.581

GnomAD2 exomes AF: 0.491 AC: 64019 AN: 130412 AF XY: 0.487

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.505 AC: 152056 AN: 301078 Hom.: 39558 Cov.: 0 AF XY: 0.498 AC XY: 85415 AN XY: 171490

African (AFR) AF: 0.729 AC: 6237 AN: 8552

American (AMR) AF: 0.466 AC: 12690 AN: 27256

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 5966 AN: 10774

East Asian (EAS) AF: 0.302 AC: 2772 AN: 9192

South Asian (SAS) AF: 0.423 AC: 25245 AN: 59626

European-Finnish (FIN) AF: 0.470 AC: 5804 AN: 12358

Middle Eastern (MID) AF: 0.603 AC: 692 AN: 1148

European-Non Finnish (NFE) AF: 0.540 AC: 85406 AN: 158150

Other (OTH) AF: 0.517 AC: 7244 AN: 14022

GnomAD4 genome AF: 0.567 AC: 86235 AN: 152012 Hom.: 25473 Cov.: 31 AF XY: 0.557 AC XY: 41408 AN XY: 74296

African (AFR) AF: 0.724 AC: 30030 AN: 41456

American (AMR) AF: 0.503 AC: 7673 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1848 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1542 AN: 5170

South Asian (SAS) AF: 0.390 AC: 1878 AN: 4820

European-Finnish (FIN) AF: 0.464 AC: 4892 AN: 10542

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36449 AN: 67974

Other (OTH) AF: 0.582 AC: 1225 AN: 2106

Alfa AF: 0.493 Hom.: 2539

Bravo AF: 0.581

Asia WGS AF: 0.384 AC: 1336 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.86
DANN	Benign	0.73
PhyloP100		-0.28
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: rs877710; hg19: chr12-109993976; COSMIC: COSV57171067; COSMIC: COSV57171067;