chr1-45507452-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_015506.3(MMACHC):c.178G>C(p.Asp60His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,614,128 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D60D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 171 hom., cov: 31)

Exomes 𝑓: 0.0026 ( 165 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_015506.3

BP4

Computational evidence support a benign effect (MetaRNN=0.003980756).

BP6

Variant 1-45507452-G-C is Benign according to our data. Variant chr1-45507452-G-C is described in ClinVar as [Benign]. Clinvar id is 138238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45507452-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.178G>C	p.Asp60His	missense_variant	Exon 2 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.7G>C	p.Asp3His	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.178G>C	p.Asp60His	missense_variant	Exon 2 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 link	c.7G>C	p.Asp3His	missense_variant	Exon 2 of 5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3936

AN:

152126

Hom.:

171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0906

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00637

AC:

1590

AN:

249514

Hom.:

AF XY:

0.00488

AC XY:

660

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.0907

Gnomad AMR exome

AF:

0.00420

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00260

AC:

3800

AN:

1461884

Hom.:

165

Cov.:

AF XY:

0.00222

AC XY:

1617

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0933

Gnomad4 AMR exome

AF:

0.00483

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.00523

GnomAD4 genome

AF:

0.0258

AC:

3934

AN:

152244

Hom.:

171

Cov.:

AF XY:

0.0255

AC XY:

1895

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0903

Gnomad4 AMR

AF:

0.00909

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00404

Hom.:

Bravo

AF:

0.0292

ESP6500AA

AF:

0.0837

AC:

346

ESP6500EA

AF:

0.000355

AC:

ExAC

AF:

0.00769

AC:

931

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 06, 2013

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. -

Apr 15, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MMACHC c.178G>C (p.Asp60His) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 2372/277122 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.091049 (2185/23998, including 96 homozygotes). This frequency is about 30 times the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cobalamin C disease

Benign:3

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0040

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;.

Vest4

0.67

MVP

0.98

MPC

0.074

ClinPred

0.010

GERP RS

5.4

Varity_R

0.63

gMVP

0.66

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