rs398124434

Variant names:

• chr12-109561056-G-A
• rs398124434
• NM_052845.4:c.568C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109561056-G-A
• chr12-109561056-G-C
• chr12-109561056-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000545712.7(MMAB):​c.568C>T​(p.Arg190Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000989 in 1,415,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: MMAB ENST00000545712.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.15
• Publications: 9 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000545712.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109561055-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 203819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 12-109561056-G-A is Pathogenic according to our data. Variant chr12-109561056-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000545712.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.568C>T	p.Arg190Cys	missense	Exon 7 of 9	NP_443077.1
	MMAB	NR_038118.2		n.679C>T		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.568C>T	p.Arg190Cys	missense	Exon 7 of 9	ENSP00000445920.1
	MMAB	ENST00000540016.5	TSL:3	c.412C>T	p.Arg138Cys	missense	Exon 5 of 7	ENSP00000474582.1
	MMAB	ENST00000537496.5	TSL:2	n.*133C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000444793.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248952 AF XY: 0.0000222

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: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000989 AC: 14 AN: 1415906 Hom.: 0 Cov.: 35 AF XY: 0.0000128 AC XY: 9 AN XY: 704076

African (AFR) AF: 0.00 AC: 0 AN: 32156

American (AMR) AF: 0.00 AC: 0 AN: 43310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24408

East Asian (EAS) AF: 0.00 AC: 0 AN: 36618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1083646

Other (OTH) AF: 0.00 AC: 0 AN: 57354

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000498 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Methylmalonic aciduria, cblB type (7)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Loss of MoRF binding (P = 0.0011)
MVP		0.98
MPC		0.98
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs398124434; hg19: chr12-109998861; COSMIC: COSV57169694; COSMIC: COSV57169694;