rs36013132

Variant names:

• chr12-109573424-GC-TT
• rs36013132
• NM_052845.4:c.56_57delGCinsAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_052845.4(MMAB):​c.56_57delGCinsAA​(p.Arg19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.273 in 72,360 alleles, including 10,289 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19H) has been classified as Benign.

• Frequency: GnomAD MNV: 𝑓 0.27 Genomes: not found (cov: 32)
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.26
• 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]

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
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -16 ACMG points.

• BP6: Variant 12-109573424-GC-TT is Benign according to our data. Variant chr12-109573424-GC-TT is described in ClinVar as Benign. ClinVar VariationId is 219003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdMnv highest population allele frequency = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.56_57delGCinsAA	p.Arg19Gln	missense_variant		ENST00000545712.7	NP_443077.1
MVK	XM_047428873.1	c.139_140delGCinsTT	p.Ala47Leu	missense_variant			XP_047284829.1
MMAB	NR_038118.2	n.80_81delGCinsAA		non_coding_transcript_exon_variant	Exon 1 of 10
MVK	XM_017019313.3	c.-162_-161delGCinsTT		5_prime_UTR_variant	Exon 1 of 10		XP_016874802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.56_57delGCinsAA	p.Arg19Gln	missense_variant		1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.273 AC: 72360 Hom.: 10289

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:2

Dec 21, 2016

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12471062, 23707710, 15308131) -

Dec 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MMAB c.56_57delinsAA (p.Arg19delinsGln) variant is an in-frame delins variant in non-repetitive region which leads to a conservative change from Arg to Gln. The genomic variants 12:110011229 G / T and 12:110011230 C / T when combined give the variant of interest. These genomic variants have allele frequency of 0.2904 (29212/100576 chromosomes) and 0.2902 (29170/100504 chromosomes) respectively in ExAC. In African sub-cohort, these changes have the exactly the same allele frequency 0.433 (3570/8244 chromosomes with 701 homozygotes), strongly supporting that these changes are in same allele resulting into the c.56_57delinsAA variant. A published study also found this variants allele frequency at 36% (Dobson_2002). These data prove that this delins variant is a common benign polymorphism. It was also found in patients who already had biallelic pathogenic variants (Dobson_2002, Yang_2004). Taken together, this variant is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36013132; hg19: chr12-110011229; COSMIC: COSV107994106; COSMIC: COSV107994106;