6-49431566-T-G

Variant names:

• chr6-49431566-T-G
• rs886061557
• NM_000255.4:c.*162A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000255.4(MMUT):​c.*162A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 516,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: MMUT NM_000255.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.289
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.*162A>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.*162A>C		3_prime_UTR_variant	Exon 13 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.*162A>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000580 AC: 3 AN: 516810 Hom.: 0 Cov.: 7 AF XY: 0.0000109 AC XY: 3 AN XY: 274432

African (AFR) AF: 0.00 AC: 0 AN: 13010

American (AMR) AF: 0.00 AC: 0 AN: 19104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13334

East Asian (EAS) AF: 0.0000706 AC: 2 AN: 28340

South Asian (SAS) AF: 0.0000208 AC: 1 AN: 48074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1918

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 327728

Other (OTH) AF: 0.00 AC: 0 AN: 26316

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.30
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs886061557; hg19: chr6-49399279;