NM_052845.4:c.134+286T>C

Variant names:

• chr12-109573061-A-G
• rs12314392
• NM_052845.4:c.134+286T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_052845.4(MMAB):​c.134+286T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,080 control chromosomes in the GnomAD database, including 18,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.48 (18057 hom., cov: 32)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65
• Publications: 16 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]

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK Gene-Disease associations (from GenCC):

• porokeratosis 3, disseminated superficial actinic type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mevalonate kinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-109573061-A-G is Benign according to our data. Variant chr12-109573061-A-G is described in ClinVar as Benign. ClinVar VariationId is 680635.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 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.134+286T>C		intron	N/A	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.158+286T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.134+286T>C		intron	N/A	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.134+286T>C		intron	N/A	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.134+286T>C		intron	N/A	ENSP00000548579.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72803 AN: 151962 Hom.: 18026 Cov.: 32

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.490

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.479 AC: 72896 AN: 152080 Hom.: 18057 Cov.: 32 AF XY: 0.472 AC XY: 35081 AN XY: 74330

African (AFR) AF: 0.594 AC: 24647 AN: 41460

American (AMR) AF: 0.452 AC: 6898 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1642 AN: 3472

East Asian (EAS) AF: 0.273 AC: 1409 AN: 5170

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4830

European-Finnish (FIN) AF: 0.397 AC: 4198 AN: 10584

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30820 AN: 67980

Other (OTH) AF: 0.491 AC: 1037 AN: 2114

Alfa AF: 0.467 Hom.: 36194

Bravo AF: 0.491

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.48
DANN	Benign	0.62
PhyloP100		-1.6
PromoterAI		0.0048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs12314392; hg19: chr12-110010866;