Genetic Variant NM_015506.3:c.181C>G (chr1-45507455-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_015506.3(MMACHC):c.181C>G(p.Arg61Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R61W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.24

Variant links:

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MMACHC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 51 pathogenic changes around while only 14 benign (78%) in NM_015506.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45507456-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 854802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25217056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.181C>G	p.Arg61Gly	missense_variant	Exon 2 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.10C>G	p.Arg4Gly	missense_variant	Exon 2 of 4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.181C>G	p.Arg61Gly	missense_variant	Exon 2 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 link	c.10C>G	p.Arg4Gly	missense_variant	Exon 2 of 5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.2

D;.

REVEL

Benign

0.25

Sift

Benign

0.12

T;.

Sift4G

Benign

0.084

T;T

Polyphen

0.083

B;.

Vest4

0.31

MutPred

0.28

Loss of methylation at K64 (P = 0.0475);.;

MVP

0.91

MPC

0.014

ClinPred

0.56

GERP RS

4.4

Varity_R

0.33

gMVP

0.43

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over