chr1-45509177-A-G

Position:

chr1-45509177-A-G

Variant summary

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

The NM_015506.3(MMACHC):c.811A>G(p.Ser271Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,613,884 control chromosomes in the GnomAD database, including 1,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S271S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.046 ( 566 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 501 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.32

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 chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 50 pathogenic changes around while only 14 benign (78%) in NM_015506.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0017081201).

BP6

Variant 1-45509177-A-G is Benign according to our data. Variant chr1-45509177-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45509177-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3 linkuse as main transcript	c.811A>G	p.Ser271Gly	missense_variant	4/4	ENST00000401061.9
MMACHC	NM_001330540.2 linkuse as main transcript	c.640A>G	p.Ser214Gly	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9 linkuse as main transcript	c.811A>G	p.Ser271Gly	missense_variant	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1 linkuse as main transcript	c.640A>G	p.Ser214Gly	missense_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.0457

AC:

6942

AN:

151994

Hom.:

567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0340

GnomAD3 exomes

AF:

0.0112

AC:

2798

AN:

249008

Hom.:

204

AF XY:

0.00865

AC XY:

1169

AN XY:

135190

show subpopulations

Gnomad AFR exome

AF:

0.159

Gnomad AMR exome

AF:

0.00763

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00613

GnomAD4 exome

AF:

0.00468

AC:

6838

AN:

1461772

Hom.:

501

Cov.:

AF XY:

0.00401

AC XY:

2913

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.165

Gnomad4 AMR exome

AF:

0.00879

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.0457

AC:

6949

AN:

152112

Hom.:

566

Cov.:

AF XY:

0.0449

AC XY:

3343

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.159

Gnomad4 AMR

AF:

0.0174

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.0337

Alfa

AF:

0.0144

Hom.:

151

Bravo

AF:

0.0515

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.142

AC:

529

ESP6500EA

AF:

0.000366

AC:

ExAC

AF:

0.0134

AC:

1614

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2020	Variant summary: MMACHC c.811A>G (p.Ser271Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 280360 control chromosomes, predominantly at a frequency of 0.16 within the African or African-American subpopulation in the gnomAD database, including 323 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cobalamin C disease

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.080

N;.

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.059

T;T

Polyphen

0.0

B;.

Vest4

0.11

MPC

0.011

ClinPred

0.064

GERP RS

2.6

Varity_R

0.11

gMVP

0.44

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