rs115802744

Variant names:

• chr12-109571660-G-A
• rs115802744
• NM_052845.4:c.185C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109571660-G-A
• chr12-109571660-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052845.4(MMAB):​c.185C>T​(p.Thr62Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,054 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T62A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (12 hom.)
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 8.15
• Publications: 5 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 -17 ACMG points.

• PM1: In a chain Corrinoid adenosyltransferase MMAB (size 217) in uniprot entity MMAB_HUMAN there are 29 pathogenic changes around while only 7 benign (81%) in NM_052845.4
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015129507).
• BP6: Variant 12-109571660-G-A is Benign according to our data. Variant chr12-109571660-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203817.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 = 0.0061 (929/152282) while in subpopulation AFR AF = 0.0214 (888/41554). AF 95% confidence interval is 0.0202. There are 19 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.185C>T	p.Thr62Met	missense	Exon 2 of 9	NP_443077.1
	MMAB	NR_038118.2		n.209C>T		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.185C>T	p.Thr62Met	missense	Exon 2 of 9	ENSP00000445920.1
	MMAB	ENST00000878519.1		c.185C>T	p.Thr62Met	missense	Exon 2 of 10	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.185C>T	p.Thr62Met	missense	Exon 2 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 917 AN: 152164 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 251454 AF XY: 0.00138

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000754 AC: 1102 AN: 1461772 Hom.: 12 Cov.: 31 AF XY: 0.000672 AC XY: 489 AN XY: 727198

African (AFR) AF: 0.0257 AC: 859 AN: 33466

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111930

Other (OTH) AF: 0.00205 AC: 124 AN: 60388

GnomAD4 genome AF: 0.00610 AC: 929 AN: 152282 Hom.: 19 Cov.: 32 AF XY: 0.00606 AC XY: 451 AN XY: 74472

African (AFR) AF: 0.0214 AC: 888 AN: 41554

American (AMR) AF: 0.00150 AC: 23 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

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

Alfa AF: 0.00195 Hom.: 10

Bravo AF: 0.00688

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Methylmalonic aciduria, cblB type (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hyperimmunoglobulin D with periodic fever (1)
-	-	1	Mevalonic aciduria (1)
-	-	1	MMAB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.64
MVP		1.0
MPC		0.85
ClinPred		0.13	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.63
Mutation Taster		=239/61	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115802744; hg19: chr12-110009465; COSMIC: COSV99031330; COSMIC: COSV99031330;