Genetic Variant NM_015702.3:c.746A>T (chr2-149570119-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_015702.3(MMADHC):c.746A>T(p.Tyr249Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y249C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.03

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-149570119-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.33113497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3 link	c.746A>T	p.Tyr249Phe	missense_variant	Exon 8 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.746A>T	p.Tyr249Phe	missense_variant	Exon 8 of 8	1	NM_015702.3	ENSP00000301920.5	Q9H3L0
MMADHC	ENST00000422782.2 link	c.848A>T	p.Tyr283Phe	missense_variant	Exon 9 of 9	5		ENSP00000408331.2	F8WEC0
MMADHC	ENST00000428879.5 link	c.746A>T	p.Tyr249Phe	missense_variant	Exon 7 of 7	2		ENSP00000389060.1	Q9H3L0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111870

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;T;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.7

L;L;.

PhyloP100

4.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.51

P;P;P

Vest4

0.39

MutPred

0.67

.;.;Gain of helix (P = 0.1736);

MVP

0.60

MPC

0.14

ClinPred

0.78

GERP RS

5.0

Varity_R

0.44

gMVP

0.42

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over