6-49457801-C-T

Position:

• chr6-49457801-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000255.4(MMUT):​c.643G>A​(p.Gly215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G215C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr6-49457801-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 6-49457801-C-T is Pathogenic according to our data. Variant chr6-49457801-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1888.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.643G>A	p.Gly215Ser	missense_variant	3/13	ENST00000274813.4
MMUT	XM_005249143.4	c.643G>A	p.Gly215Ser	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.643G>A	p.Gly215Ser	missense_variant	3/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461344 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2023

ClinVar contains an entry for this variant (Variation ID: 1888). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly215 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 26790480). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 15643616, 16281286, 16451139, 24059531, 26615597). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 215 of the MUT protein (p.Gly215Ser). -

METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MutPred		0.96		Loss of methylation at K212 (P = 0.0739);
MVP		0.99
MPC		0.48
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs121918258; hg19: chr6-49425514;