rs147370143

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_015702.3(MMADHC):c.578T>C(p.Val193Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,604,280 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 3 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 8.52

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

inborn disorder of cobalamin metabolism and transport
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
methylmalonic aciduria and homocystinuria type cblD
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

MMADHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083274096).

BP6

Variant 2-149575742-A-G is Benign according to our data. Variant chr2-149575742-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285847.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00115 (175/152320) while in subpopulation NFE AF = 0.00198 (135/68020). AF 95% confidence interval is 0.00171. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015702.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	NM_015702.3	MANE Select	c.578T>C	p.Val193Ala	missense	Exon 6 of 8	NP_056517.1	Q9H3L0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.578T>C	p.Val193Ala	missense	Exon 6 of 8	ENSP00000301920.5	Q9H3L0
MMADHC	ENST00000934249.1		c.701T>C	p.Val234Ala	missense	Exon 7 of 9	ENSP00000604308.1
MMADHC	ENST00000422782.2	TSL:5	c.578T>C	p.Val193Ala	missense	Exon 6 of 9	ENSP00000408331.2	F8WEC0

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00178

AC:

435

AN:

244924

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000912

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00185

GnomAD4 exome

AF:

0.00174

AC:

2528

AN:

1451960

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1254

AN XY:

722192

show subpopulations

African (AFR)

AF:

0.000302

AC:

AN:

33144

American (AMR)

AF:

0.000116

AC:

AN:

43278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

39442

South Asian (SAS)

AF:

0.00172

AC:

145

AN:

84344

European-Finnish (FIN)

AF:

0.00248

AC:

132

AN:

53186

Middle Eastern (MID)

AF:

0.000542

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.00193

AC:

2134

AN:

1107282

Other (OTH)

AF:

0.00165

AC:

AN:

60014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

116

232

347

463

579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152320

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00198

AC:

135

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.00116

AC:

AN:

3462

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria and homocystinuria type cblD (3)

not provided (3)

Disorders of Intracellular Cobalamin Metabolism (1)

MMADHC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.078

MetaRNN

Benign

0.083

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.4

PhyloP100

8.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.62

Sift

Uncertain

0.014

Sift4G

Benign

0.13

Polyphen

0.51

Vest4

0.82

MVP

0.86

MPC

0.058

ClinPred

0.050

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.41

gMVP

0.47

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over