chr6-49444562-T-G

Variant names:

• chr6-49444562-T-G
• rs9381786
• NM_000255.4:c.1676+77A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

MMUT Gene-Disease associations (from GenCC):

• methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• vitamin B12-unresponsive methylmalonic acidemia type mut-

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• vitamin B12-unresponsive methylmalonic acidemia type mut0

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 498783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.1676+77A>C		intron	N/A	NP_000246.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.1676+77A>C		intron	N/A	ENSP00000274813.3

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

African (AFR) AF: 0.165 AC: 4147 AN: 25128

American (AMR) AF: 0.126 AC: 5539 AN: 43936

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4412 AN: 23334

East Asian (EAS) AF: 0.207 AC: 7801 AN: 37646

South Asian (SAS) AF: 0.284 AC: 21970 AN: 77406

European-Finnish (FIN) AF: 0.229 AC: 11315 AN: 49328

Middle Eastern (MID) AF: 0.291 AC: 1429 AN: 4918

European-Non Finnish (NFE) AF: 0.254 AC: 182401 AN: 719120

Other (OTH) AF: 0.241 AC: 11100 AN: 46036

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

African (AFR) AF: 0.166 AC: 6890 AN: 41470

American (AMR) AF: 0.174 AC: 2652 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 650 AN: 3472

East Asian (EAS) AF: 0.241 AC: 1243 AN: 5166

South Asian (SAS) AF: 0.277 AC: 1337 AN: 4824

European-Finnish (FIN) AF: 0.230 AC: 2430 AN: 10580

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17383 AN: 67982

Other (OTH) AF: 0.218 AC: 459 AN: 2106

Alfa AF: 0.244 Hom.: 2489

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 21671183)

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 06, 2017

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

Aug 28, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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