rs2287180

Variant names:

• chr12-109561263-G-A
• rs2287180
• NM_052845.4:c.519+157C>T

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.519+157C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,583,266 control chromosomes in the GnomAD database, including 23,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2258 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21717 hom.)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.288
• Publications: 8 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=-0.81).
• BP6: Variant 12-109561263-G-A is Benign according to our data. Variant chr12-109561263-G-A is described in ClinVar as Benign. ClinVar VariationId is 680637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.519+157C>T		intron	N/A	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.610C>T		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.519+157C>T		intron	N/A	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.582+157C>T		intron	N/A	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.519+157C>T		intron	N/A	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25731 AN: 152032 Hom.: 2262 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0989

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.165 AC: 34166 AN: 207258 AF XY: 0.164

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.173 AC: 247096 AN: 1431116 Hom.: 21717 Cov.: 34 AF XY: 0.171 AC XY: 121581 AN XY: 711236

African (AFR) AF: 0.184 AC: 6085 AN: 33048

American (AMR) AF: 0.146 AC: 6149 AN: 42166

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4935 AN: 25920

East Asian (EAS) AF: 0.157 AC: 6069 AN: 38776

South Asian (SAS) AF: 0.138 AC: 11621 AN: 84412

European-Finnish (FIN) AF: 0.109 AC: 4097 AN: 37442

Middle Eastern (MID) AF: 0.192 AC: 1106 AN: 5758

European-Non Finnish (NFE) AF: 0.178 AC: 196772 AN: 1103860

Other (OTH) AF: 0.172 AC: 10262 AN: 59734

GnomAD4 genome AF: 0.169 AC: 25738 AN: 152150 Hom.: 2258 Cov.: 32 AF XY: 0.163 AC XY: 12161 AN XY: 74382

African (AFR) AF: 0.188 AC: 7803 AN: 41488

American (AMR) AF: 0.156 AC: 2389 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3468

East Asian (EAS) AF: 0.138 AC: 710 AN: 5156

South Asian (SAS) AF: 0.130 AC: 627 AN: 4830

European-Finnish (FIN) AF: 0.0989 AC: 1049 AN: 10612

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11883 AN: 67986

Other (OTH) AF: 0.174 AC: 368 AN: 2114

Alfa AF: 0.176 Hom.: 444

Bravo AF: 0.176

Asia WGS AF: 0.150 AC: 523 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.81
CADD	Benign	9.8
DANN	Benign	0.92
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2287180; hg19: chr12-109999068; COSMIC: COSV57170036; COSMIC: COSV57170036;