Menu
GeneBe

2-149569996-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015702.3(MMADHC):ā€‹c.869T>Gā€‹(p.Met290Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,220 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 Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

8
9
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.93
Variant links:
Genes affected
MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MMADHCNM_015702.3 linkuse as main transcriptc.869T>G p.Met290Arg missense_variant 8/8 ENST00000303319.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MMADHCENST00000303319.10 linkuse as main transcriptc.869T>G p.Met290Arg missense_variant 8/81 NM_015702.3 P1
MMADHCENST00000422782.2 linkuse as main transcriptc.971T>G p.Met324Arg missense_variant 9/95
MMADHCENST00000428879.5 linkuse as main transcriptc.869T>G p.Met290Arg missense_variant 7/72 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251322
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135844
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461220
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726916
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 04, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;D;D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Uncertain
2.9
M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
0.93
P;P;D
Vest4
0.91
MutPred
0.74
.;.;Loss of ubiquitination at K325 (P = 0.0134);
MVP
0.85
MPC
0.21
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1401528755; hg19: chr2-150426510; API