Variant rs118204045 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_015702.3(MMADHC):c.545C>A(p.Thr182Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,816 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.14

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]

MMADHC links:

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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, 0.84

PP5

Variant 2-149575775-G-T is Pathogenic according to our data. Variant chr2-149575775-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 762.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3 linkuse as main transcript	c.545C>A	p.Thr182Asn	missense_variant	6/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MMADHC	ENST00000303319.10 linkuse as main transcript	c.545C>A	p.Thr182Asn	missense_variant	6/8	1	NM_015702.3	ENSP00000301920	P1
MMADHC	ENST00000422782.2 linkuse as main transcript	c.545C>A	p.Thr182Asn	missense_variant	6/9	5		ENSP00000408331
MMADHC	ENST00000428879.5 linkuse as main transcript	c.545C>A	p.Thr182Asn	missense_variant	5/7	2		ENSP00000389060	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456816

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblD TYPE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 03, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.82

P;P;P

Vest4

0.96

MutPred

0.52

Loss of phosphorylation at T182 (P = 0.0187);Loss of phosphorylation at T182 (P = 0.0187);Loss of phosphorylation at T182 (P = 0.0187);

MVP

0.85

MPC

0.052

ClinPred

0.99

GERP RS

4.5

Varity_R

0.82

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over