chr12-109573424-GC-TT

Position:

• chr12-109573424-GC-TT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_052845.4(MMAB):​c.56_57delinsAA​(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. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19H) has been classified as Benign.

• Frequency: 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-109573424-GC-TT is Benign according to our data. Variant chr12-109573424-GC-TT is described in ClinVar as [Benign]. Clinvar id is 219003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAB	NM_052845.4	c.56_57delinsAA	p.Arg19Gln	missense_variant	1/9	ENST00000545712.7	NP_443077.1
MVK	XM_047428873.1	c.139_140delinsTT	p.Ala47Leu	missense_variant	1/11		XP_047284829.1
MVK	XM_017019313.3	c.-162_-161delinsTT		5_prime_UTR_variant	1/10		XP_016874802.1
MMAB	NR_038118.2	n.80_81delinsAA		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.56_57delinsAA	p.Arg19Gln	missense_variant	1/9	1	NM_052845.4	ENSP00000445920	P1

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

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:2

Likely benign, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Dec 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	This variant is associated with the following publications: (PMID: 12471062, 23707710, 15308131) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2016	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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs36013132; hg19: chr12-110011229;