rs776804847

Variant names:

• chr12-109553763-T-C
• rs776804847
• NM_052845.4:c.*3265A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_052845.4(MMAB):​c.*3265A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 426,196 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (2 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000512 (78/152340) while in subpopulation AMR AF = 0.00235 (36/15308). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*3265A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.*3265A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000678 AC: 79 AN: 116540 AF XY: 0.000757

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.000877

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000551 AC: 151 AN: 273856 Hom.: 2 Cov.: 0 AF XY: 0.000603 AC XY: 93 AN XY: 154128

African (AFR) AF: 0.000135 AC: 1 AN: 7434

American (AMR) AF: 0.00149 AC: 36 AN: 24208

Ashkenazi Jewish (ASJ) AF: 0.000731 AC: 7 AN: 9574

East Asian (EAS) AF: 0.00 AC: 0 AN: 8740

South Asian (SAS) AF: 0.000732 AC: 41 AN: 55976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11628

Middle Eastern (MID) AF: 0.00882 AC: 9 AN: 1020

European-Non Finnish (NFE) AF: 0.000344 AC: 49 AN: 142610

Other (OTH) AF: 0.000632 AC: 8 AN: 12666

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74486

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.00235 AC: 36 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.000457

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblB type Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		2.2
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: rs776804847; hg19: chr12-109991568;