1-45509214-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_015506.3(MMACHC):c.848G>T(p.Ter283Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,930 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. *283*) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 4 hom. )

Consequence

MMACHC
NM_015506.3 stop_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 1.35

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Stoplost variant in NM_015506.3 Downstream stopcodon found after 293 codons.

BP6

Variant 1-45509214-G-T is Benign according to our data. Variant chr1-45509214-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197306.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=3}.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000224 (328/1461786) while in subpopulation AMR AF = 0.00727 (325/44720). AF 95% confidence interval is 0.00662. There are 4 homozygotes in GnomAdExome4. There are 114 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.848G>T	p.Ter283Leuext*?	stop_lost	Exon 4 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.677G>T	p.Ter226Leuext*?	stop_lost	Exon 4 of 4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMACHC	ENST00000401061.9 link	c.848G>T	p.Ter283Leuext*?	stop_lost	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4	Q9Y4U1
MMACHC	ENST00000616135.1 link	c.677G>T	p.Ter226Leuext*?	stop_lost	Exon 4 of 5	2		ENSP00000478859.1	A0A0C4DGU2
MMACHC	ENST00000477188.1 link	n.-219G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

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:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00112

AC:

277

AN:

248412

AF XY:

0.000756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00803

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

328

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00727

AC:

325

AN:

44720

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86240

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53348

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1112006

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000289

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00275

AC:

0.00275085

AN:

0.00275085

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147054

AN:

0.0000147054

Gnomad4 OTH

AF:

0.000475

AC:

0.000474834

AN:

0.000474834

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000169

Hom.:

Bravo

AF:

0.000661

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000770

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cobalamin C disease

Uncertain:2Benign:2

Feb 17, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 30, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 10, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Uncertain:1Benign:1

Jan 26, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 24, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MMACHC c.848G>T (p.X283LeuextX14) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MMACHC c.848G>T (p.X283LeuextX14) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0011 in 248412 control chromosomes, predominantly at a frequency of 0.008 within the Latino subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.848G>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (n=3) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign. -

MMACHC-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Methylmalonic acidemia with homocystinuria cblC

Benign:1

Apr 30, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.76

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.82

Vest4

0.082

GERP RS

3.5

Mutation Taster

=137/63

disease causing (ClinVar)

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