rs483352778

Positions:

chr6-49459144-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.323G>A(p.Arg108His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.50

Variant links:

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMUT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 5) in uniprot entity MUTA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000255.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 6-49459144-C-T is Pathogenic according to our data. Variant chr6-49459144-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.323G>A	p.Arg108His	missense_variant	2/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4 linkuse as main transcript	c.323G>A	p.Arg108His	missense_variant	2/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.323G>A	p.Arg108His	missense_variant	2/13	1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251292

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 03, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PM2_P+PM3_VS+PP3+PP4 -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 108 of the MUT protein (p.Arg108His). This variant is present in population databases (rs483352778, gnomAD 0.007%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 11528502, 16281286, 17113806). ClinVar contains an entry for this variant (Variation ID: 100707). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. This variant disrupts the p.Arg108 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2661559, 16281286, 17075691, 22614770, 23045948, 24059531, 24464670, 27578510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Medical Genetics Unit, Ain Shams University Pediatrics Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17113806, 17075691, 25959030, 26454439, 25750861, 16435223, 27233228, 22661206, 23430940, 31466887, 35361390, 15643616, 21671183, 30098236, 31622506, 33413471, 33453710, 35223700, 11528502, 29731766, 32005694, 31998365, 27167370, 16281286, 26018627, 32754920) -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Methylmalonic acidemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 10, 2017

Variant summary: The MUT c.323G>A (p.Arg108His) variant involves the alteration of a conserved nucleotide located at the SB, substrate binding (beta alpha) 8 barrel domain (Lempp_2007). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/246336 control chromosomes at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been reported in multiple affected individuals mostly as compound heterozygotes and the patients' fibroblasts presented with a marked decrease in MCM enzyme activity (Acquaviva_2001 and Lempp_2007). Variants involving codon R108 (p.R108C, p.R108G, and p.R108H) have been reported in multiple patients with Methylmalonic aciduria suggesting it is a mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

METHYLMALONIC ACIDURIA, mut(0) TYPE

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.98

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.98

MutPred

1.0

Loss of MoRF binding (P = 0.0708);

MVP

0.98

MPC

0.54

ClinPred

1.0

GERP RS

5.6

gMVP

0.93

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