chr6-49459465-A-G

Variant names:

• chr6-49459465-A-G
• rs879253820
• NM_000255.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000255.4(MMUT):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000343 in 1,457,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MMUT NM_000255.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.45
• Publications: 5 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 22 pathogenic variants. Next in-frame start position is after 79 codons. Genomic position: 49459232. Lost 0.104 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-49459465-A-G is Pathogenic according to our data. Variant chr6-49459465-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 222903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457672 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725320

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 27, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

-

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.66	D
PhyloP100		6.5
PROVEAN	Benign	-0.72	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.95
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0286);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.73
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs879253820; hg19: chr6-49427178;