rs62000414

Variant names:

• chr12-109568772-A-G
• rs62000414
• NM_052845.4:c.288T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-109568772-A-G
• chr12-109568772-A-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_052845.4(MMAB):​c.288T>C​(p.Ile96Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,612,942 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (437 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (358 hom.)
• Consequence: MMAB NM_052845.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003791
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.266
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-109568772-A-G is Benign according to our data. Variant chr12-109568772-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.266 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.288T>C	p.Ile96Ile	splice_region synonymous	Exon 3 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.312T>C		splice_region non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.288T>C	p.Ile96Ile	splice_region synonymous	Exon 3 of 9	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.288T>C	p.Ile96Ile	splice_region synonymous	Exon 3 of 10	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.288T>C	p.Ile96Ile	splice_region synonymous	Exon 3 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5906 AN: 152122 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0102 AC: 2573 AN: 251488 AF XY: 0.00751

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00395 AC: 5776 AN: 1460702 Hom.: 358 Cov.: 31 AF XY: 0.00334 AC XY: 2424 AN XY: 726704

African (AFR) AF: 0.134 AC: 4479 AN: 33414

American (AMR) AF: 0.00937 AC: 419 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5766

European-Non Finnish (NFE) AF: 0.000265 AC: 294 AN: 1110968

Other (OTH) AF: 0.00878 AC: 530 AN: 60354

GnomAD4 genome AF: 0.0389 AC: 5916 AN: 152240 Hom.: 437 Cov.: 33 AF XY: 0.0372 AC XY: 2767 AN XY: 74450

African (AFR) AF: 0.135 AC: 5616 AN: 41514

American (AMR) AF: 0.0139 AC: 212 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68010

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0190 Hom.: 80

Bravo AF: 0.0433

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.2
DANN	Benign	0.66
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=266/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0040
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: rs62000414; hg19: chr12-110006577;