6-49435588-C-T

Position:

• chr6-49435588-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000255.4(MMUT):​c.1992G>A​(p.Ala664Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,613,886 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (299 hom.)
• Consequence: MMUT NM_000255.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.123

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 6-49435588-C-T is Benign according to our data. Variant chr6-49435588-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1992G>A	p.Ala664Ala	synonymous_variant	12/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1992G>A	p.Ala664Ala	synonymous_variant	12/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1992G>A	p.Ala664Ala	synonymous_variant	12/13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1341 AN: 152146 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0686

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0171 AC: 4298 AN: 250878 Hom.: 233 AF XY: 0.0130 AC XY: 1763 AN XY: 135592

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0291

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00424 AC: 6200 AN: 1461622 Hom.: 299 Cov.: 33 AF XY: 0.00372 AC XY: 2702 AN XY: 727094

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.0998

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0329

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00885 AC: 1348 AN: 152264 Hom.: 56 Cov.: 32 AF XY: 0.0103 AC XY: 765 AN XY: 74446

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0689

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00250 Hom.: 6

Bravo AF: 0.0138

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2013	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.70

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: rs144146728; hg19: chr6-49403301;