rs1164271240

Positions:

• chr6-49435560-G-A
• chr6-49435560-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000255.4(MMUT):​c.2020C>T​(p.Leu674Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.26

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain B12-binding (size 132) in uniprot entity MUTA_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000255.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 6-49435560-G-A is Pathogenic according to our data. Variant chr6-49435560-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 583274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.2020C>T	p.Leu674Phe	missense_variant	12/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.2020C>T	p.Leu674Phe	missense_variant	12/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.2020C>T	p.Leu674Phe	missense_variant	12/13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251114 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 07, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different missense substitution at this codon (p.Leu674Val) has been determined to be likely pathogenic (Invitae). This suggests that the leucine residue is critical for MUT protein function and that other missense substitutions at this position may also be deleterious. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported in the homozygous state in an individual affected with methylmalonic acidemia (PMID: 22727635). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 674 of the MUT protein (p.Leu674Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Vest4		0.92
MutPred		0.76		Gain of catalytic residue at L674 (P = 0.042);
MVP		0.98
MPC		0.49
ClinPred		0.99	D
GERP RS		4.9
gMVP		0.78

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

Other links and lift over

dbSNP: rs1164271240; hg19: chr6-49403273;