rs61746421

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015702.3(MMADHC):c.412G>A(p.Glu138Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00191 in 1,613,626 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E138D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0098 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 30 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.46

Publications

2 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: Ambry Genetics, ClinGen
methylmalonic aciduria and homocystinuria type cblD
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

MMADHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005735874).

BP6

Variant 2-149576503-C-T is Benign according to our data. Variant chr2-149576503-C-T is described in ClinVar as [Benign]. Clinvar id is 331380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00982 (1496/152282) while in subpopulation AFR AF = 0.034 (1412/41564). AF 95% confidence interval is 0.0325. There are 30 homozygotes in GnomAd4. There are 705 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 5 of 8	ENST00000303319.10	NP_056517.1	Q9H3L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMADHC	ENST00000303319.10 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 5 of 8	1	NM_015702.3	ENSP00000301920.5	Q9H3L0
MMADHC	ENST00000422782.2 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 5 of 9	5		ENSP00000408331.2	F8WEC0
MMADHC	ENST00000428879.5 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 4 of 7	2		ENSP00000389060.1	Q9H3L0

Frequencies

GnomAD3 genomes

AF:

0.00979

AC:

1489

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00259

AC:

651

AN:

251334

AF XY:

0.00196

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00108

AC:

1580

AN:

1461344

Hom.:

Cov.:

AF XY:

0.000916

AC XY:

666

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.0370

AC:

1238

AN:

33416

American (AMR)

AF:

0.00201

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000819

AC:

AN:

1111688

Other (OTH)

AF:

0.00225

AC:

136

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00982

AC:

1496

AN:

152282

Hom.:

Cov.:

AF XY:

0.00947

AC XY:

705

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0340

AC:

1412

AN:

41564

American (AMR)

AF:

0.00333

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68018

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00286

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0336

AC:

148

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00316

AC:

384

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Uncertain

-0.041

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

5.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.084

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.024

B;B;B

Vest4

0.48

MVP

0.71

MPC

0.062

ClinPred

0.014

GERP RS

5.5

Varity_R

0.50

gMVP

0.33

Mutation Taster

=85/15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over