rs1481415459

Positions:

• chr12-109573469-G-C
• chr12-109573469-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052845.4(MMAB):​c.12C>G​(p.Cys4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089794844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAB	NM_052845.4	c.12C>G	p.Cys4Trp	missense_variant	1/9	ENST00000545712.7	NP_443077.1
MVK	XM_047428873.1	c.184G>C	p.Ala62Pro	missense_variant	1/11		XP_047284829.1
MVK	XM_017019313.3	c.-117G>C		5_prime_UTR_variant	1/10		XP_016874802.1
MMAB	NR_038118.2	n.36C>G		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.12C>G	p.Cys4Trp	missense_variant	1/9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.26	T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.2	N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	2.1	N;.;.
REVEL	Benign	0.27
Sift	Benign	0.53	T;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.0	B;.;.
Vest4		0.23
MutPred		0.52		Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);
MVP		0.52
MPC		0.81
ClinPred		0.078	T
GERP RS		0.62
Varity_R		0.16
gMVP		0.67

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-110011274;