12-109561053-G-T

Variant names:

• chr12-109561053-G-T
• rs376128990
• NM_052845.4:c.571C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_052845.4(MMAB):​c.571C>A​(p.Arg191Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,366,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R191R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MMAB NM_052845.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 20 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.

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.571C>A	p.Arg191Arg	synonymous	Exon 7 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.682C>A		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.571C>A	p.Arg191Arg	synonymous	Exon 7 of 9	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.634C>A	p.Arg212Arg	synonymous	Exon 8 of 10	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.571C>A	p.Arg191Arg	synonymous	Exon 7 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248708 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000503

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1366014 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 678826

African (AFR) AF: 0.00 AC: 0 AN: 30538

American (AMR) AF: 0.00 AC: 0 AN: 41786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22610

East Asian (EAS) AF: 0.00 AC: 0 AN: 32680

South Asian (SAS) AF: 0.00 AC: 0 AN: 85346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1051132

Other (OTH) AF: 0.00 AC: 0 AN: 53844

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000150 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.53
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs376128990; hg19: chr12-109998858;