1-45509214-G-T

Position:

chr1-45509214-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_015506.3(MMACHC):c.848G>T(p.Ter283LeuextTer14) 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:5

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 made for transcript

Verdict is Benign. Variant got -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, Benign=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 114 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3 linkuse as main transcript	c.848G>T	p.Ter283LeuextTer14	stop_lost	4/4	ENST00000401061.9
MMACHC	NM_001330540.2 linkuse as main transcript	c.677G>T	p.Ter226LeuextTer14	stop_lost	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9 linkuse as main transcript	c.848G>T	p.Ter283LeuextTer14	stop_lost	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1 linkuse as main transcript	c.677G>T	p.Ter226LeuextTer14	stop_lost	4/5	2

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

GnomAD3 exomes

AF:

0.00112

AC:

277

AN:

248412

Hom.:

AF XY:

0.000756

AC XY:

102

AN XY:

135006

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 SAS 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

Gnomad4 AMR exome

AF:

0.00727

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

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

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00000872

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:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cobalamin C disease

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 24, 2022

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 30, 2020

- -

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

MutationTaster

Benign

1.0

Vest4

0.082

GERP RS

3.5

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