rs9381786

Positions:

• chr6-49444562-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(MMUT):​c.1676+77A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,178,926 control chromosomes in the GnomAD database, including 35,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3841 hom., cov: 32)
  • Exomes 𝑓: 0.24 (31588 hom.)
• Consequence: MMUT NM_000255.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.539

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-49444562-T-G is Benign according to our data. Variant chr6-49444562-T-G is described in ClinVar as [Benign]. Clinvar id is 498783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49444562-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1676+77A>C		intron_variant		ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1676+77A>C		intron_variant			XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1676+77A>C		intron_variant		1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33392 AN: 151956 Hom.: 3838 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.244 AC: 250114 AN: 1026852 Hom.: 31588 AF XY: 0.247 AC XY: 131215 AN XY: 530514

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.284

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.220 AC: 33408 AN: 152074 Hom.: 3841 Cov.: 32 AF XY: 0.219 AC XY: 16242 AN XY: 74322

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.218

Alfa AF: 0.244 Hom.: 2231

Bravo AF: 0.211

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 21671183) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 06, 2017

- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.7
DANN	Benign	0.80

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: rs9381786; hg19: chr6-49412275; COSMIC: COSV51272669;