rs756195708

Variant names:

• chr12-109561040-C-T
• rs756195708
• NM_052845.4:c.584G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_052845.4(MMAB):​c.584G>A​(p.Arg195His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000131 in 1,608,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000917670: The variant, c.584G>A, was observed in two siblings, one presenting with Methylmalonic Acidemia, while the sibling with the same genotype was asymptomatic (Jorge-Finnigan_2010). Multiple publications have functionally assessed the variant and observed the variant to affect splicing, but does produce a limited amount of wild type protein (Jorge-Finnigan_2010), along with presenting functional implications on proper MMAB protein function (Brasil_2015).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MMAB NM_052845.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.45
• Publications: 7 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000917670: The variant, c.584G>A, was observed in two siblings, one presenting with Methylmalonic Acidemia, while the sibling with the same genotype was asymptomatic (Jorge-Finnigan_2010). Multiple publications have functionally assessed the variant and observed the variant to affect splicing, but does produce a limited amount of wild type protein (Jorge-Finnigan_2010), along with presenting functional implications on proper MMAB protein function (Brasil_2015).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_052845.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 12-109561040-C-T is Pathogenic according to our data. Variant chr12-109561040-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218322.

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.584G>A	p.Arg195His	missense splice_region	Exon 7 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.695G>A		splice_region 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.584G>A	p.Arg195His	missense splice_region	Exon 7 of 9	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.647G>A	p.Arg216His	missense splice_region	Exon 8 of 10	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.584G>A	p.Arg195Gln	missense splice_region	Exon 7 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151578 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248074 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1456432 Hom.: 0 Cov.: 36 AF XY: 0.00000690 AC XY: 5 AN XY: 724766

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110932

Other (OTH) AF: 0.0000332 AC: 2 AN: 60266

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151578 Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2 AN XY: 74004

African (AFR) AF: 0.0000728 AC: 3 AN: 41220

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000220 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Methylmalonic aciduria, cblB type (4)
1	-	-	Methylmalonic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.56
Sift	Benign	0.15	T
Sift4G	Benign	0.55	T
Polyphen		0.94	P
Vest4		0.42
MutPred		0.72		Loss of MoRF binding (P = 0.0257)
MVP		1.0
MPC		0.45
ClinPred		0.58	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.59
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		3.0
SpliceAI score (max)		0.020		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: rs756195708; hg19: chr12-109998845; COSMIC: COSV57170729; COSMIC: COSV57170729;