NM_000255.4:c.1629C>T

Variant names:

• chr6-49444686-G-A
• rs150642856
• NM_000255.4:c.1629C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000255.4(MMUT):​c.1629C>T​(p.Ser543Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,613,274 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (50 hom.)
• Consequence: MMUT NM_000255.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.122

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-49444686-G-A is Benign according to our data. Variant chr6-49444686-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92682.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}. Variant chr6-49444686-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.122 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00479 (728/152118) while in subpopulation NFE AF= 0.00785 (534/67992). AF 95% confidence interval is 0.0073. There are 5 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 9 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 9 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 9 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 728 AN: 152000 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00512 AC: 1286 AN: 251120 Hom.: 6 AF XY: 0.00549 AC XY: 745 AN XY: 135712

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.00648 AC: 9462 AN: 1461156 Hom.: 50 Cov.: 30 AF XY: 0.00654 AC XY: 4752 AN XY: 726900

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.00786

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00430

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00732

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.00479 AC: 728 AN: 152118 Hom.: 5 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74356

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00433

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00683 Hom.: 4

Bravo AF: 0.00501

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00982

EpiControl AF: 0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Uncertain:1 Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MMUT: BP4, BP7, BS2 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Apr 06, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 22, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.8
DANN	Benign	0.51

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: rs150642856; hg19: chr6-49412399;