6-49431148-T-C

Variant names:

• chr6-49431148-T-C
• rs11757098
• NM_000255.4:c.*580A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.*580A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.*580A>G		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.*580A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_000255.4	ENSP00000274813.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0714 AC: 1 AN: 14

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.102 AC: 10 AN: 98

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.0392 AC: 1629 AN: 41540

American (AMR) AF: 0.0884 AC: 1350 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3470

East Asian (EAS) AF: 0.172 AC: 888 AN: 5174

South Asian (SAS) AF: 0.187 AC: 903 AN: 4822

European-Finnish (FIN) AF: 0.0881 AC: 933 AN: 10586

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10069 AN: 67978

Other (OTH) AF: 0.109 AC: 231 AN: 2110

Alfa AF: 0.122 Hom.: 469

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.5
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: rs11757098; hg19: chr6-49398861; COSMIC: COSV51281188;