rs2270655

Positions:

chr4-145655266-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172250.3(MMAA):c.1089G>C(p.Gln363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,614,116 control chromosomes in the GnomAD database, including 3,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 282 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2884 hom. )

Consequence

MMAA
NM_172250.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.25

Variant links:

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026459396).

BP6

Variant 4-145655266-G-C is Benign according to our data. Variant chr4-145655266-G-C is described in ClinVar as [Benign]. Clinvar id is 96533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-145655266-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MMAA	NM_172250.3 linkuse as main transcript	c.1089G>C	p.Gln363His	missense_variant	7/7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1 linkuse as main transcript	c.1089G>C	p.Gln363His	missense_variant	7/7		NP_001362573.1
MMAA	XM_011531684.4 linkuse as main transcript	c.1089G>C	p.Gln363His	missense_variant	7/7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 linkuse as main transcript	c.1089G>C	p.Gln363His	missense_variant	7/7		NM_172250.3	ENSP00000497008	P1

Frequencies

GnomAD3 genomes

AF:

0.0527

AC:

8018

AN:

152128

Hom.:

284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.0874

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0545

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0503

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0643

AC:

16158

AN:

251482

Hom.:

660

AF XY:

0.0669

AC XY:

9096

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0463

Gnomad AMR exome

AF:

0.0623

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0893

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.0595

Gnomad NFE exome

AF:

0.0512

Gnomad OTH exome

AF:

0.0555

GnomAD4 exome

AF:

0.0568

AC:

82974

AN:

1461870

Hom.:

2884

Cov.:

AF XY:

0.0591

AC XY:

42986

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0444

Gnomad4 AMR exome

AF:

0.0623

Gnomad4 ASJ exome

AF:

0.0359

Gnomad4 EAS exome

AF:

0.0911

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.0603

Gnomad4 NFE exome

AF:

0.0511

Gnomad4 OTH exome

AF:

0.0530

GnomAD4 genome

AF:

0.0527

AC:

8023

AN:

152246

Hom.:

282

Cov.:

AF XY:

0.0547

AC XY:

4069

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0447

Gnomad4 AMR

AF:

0.0505

Gnomad4 ASJ

AF:

0.0403

Gnomad4 EAS

AF:

0.0872

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.0545

Gnomad4 NFE

AF:

0.0503

Gnomad4 OTH

AF:

0.0397

Alfa

AF:

0.0501

Hom.:

161

Bravo

AF:

0.0488

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.0458

AC:

202

ESP6500EA

AF:

0.0536

AC:

461

ExAC

AF:

0.0652

AC:

7921

Asia WGS

AF:

0.107

AC:

372

AN:

3478

EpiCase

AF:

0.0456

EpiControl

AF:

0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2013	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.;T;T;T;D

Eigen

Benign

-0.17

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;T;.;.;D;D

MetaRNN

Benign

0.0026

T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.3

M;.;M;M;M;.

MutationTaster

Benign

0.00060

P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.87

.;.;N;.;.;.

REVEL

Benign

0.24

Sift

Benign

0.43

.;.;T;.;.;.

Sift4G

Benign

0.17

.;.;T;.;.;T

Polyphen

0.0010

B;.;B;B;B;.

Vest4

0.10, 0.057

MutPred

0.19

Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MPC

0.11

ClinPred

0.026

GERP RS

4.8

Varity_R

0.15

gMVP

0.69

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