6-49431148-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000255.4(MMUT):c.*580A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,286 control chromosomes in the GnomAD database, including 1,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1130 hom., cov: 32)
  • Exomes 𝑓: 0.098 (1 hom.)
• Consequence: MMUT NM_000255.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-49431148-T-C is Benign according to our data. Variant chr6-49431148-T-C is described in ClinVar as [Benign]. Clinvar id is 357242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.*580A>G		3_prime_UTR_variant	13/13	ENST00000274813.4
MMUT	XM_005249143.4	c.*580A>G		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.*580A>G		3_prime_UTR_variant	13/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16511 AN: 152046 Hom.: 1130 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0881

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0984 AC: 12 AN: 122 Hom.: 1 Cov.: 0 AF XY: 0.0682 AC XY: 6 AN XY: 88

Gnomad4 EAS exome AF: 0.0714

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.108 AC: 16509 AN: 152164 Hom.: 1130 Cov.: 32 AF XY: 0.106 AC XY: 7919 AN XY: 74410

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.0884

Gnomad4 ASJ AF: 0.0957

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.0881

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.109

Alfa AF: 0.125 Hom.: 380

Bravo AF: 0.102

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.25
Dann	Benign	0.61

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: rs11757098; hg19: chr6-49398861; COSMIC: COSV51281188;