rs1554158951

Positions:

• chr6-49441858-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000255.4(MMUT):​c.1790T>G​(p.Ile597Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1790T>G	p.Ile597Arg	missense_variant	10/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1790T>G	p.Ile597Arg	missense_variant	10/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1790T>G	p.Ile597Arg	missense_variant	10/13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 30, 2024

Variant summary: MUT c.1790T>G (p.Ile597Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes (GNOMad). c.1790T>G has been reported in the literature in at least one compound heterozygous individual affected with Methylmalonic Acidemia, who also carried a second pathogenic variant (Han_2015, Han_2017, Yu_2021, Liang_2023). These data do not allow clear conclusions about variant significance. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated that the variant did not affect protein expression, but decreased its activity, resulting in about 20% of normal (Han_2017). The following publications have been ascertained in the context of this evaluation (PMID: 26454439, 28101778, 34668645, 37316190). ClinVar contains an entry for this variant (Variation ID: 551764). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.023	D
Sift4G	Benign	0.079	T
Vest4		0.96
MutPred		0.64		Gain of disorder (P = 0.0257);
MVP		1.0
MPC		0.47
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554158951; hg19: chr6-49409571;