6-49447735-C-T

Position:

• chr6-49447735-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(MMUT):​c.1495G>A​(p.Ala499Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,609,812 control chromosomes in the GnomAD database, including 9,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (818 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8316 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.422

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001824379).
• BP6: Variant 6-49447735-C-T is Benign according to our data. Variant chr6-49447735-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49447735-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1495G>A	p.Ala499Thr	missense_variant	8/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1495G>A	p.Ala499Thr	missense_variant	8/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1495G>A	p.Ala499Thr	missense_variant	8/13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15706 AN: 151522 Hom.: 817 Cov.: 32

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0810

Gnomad ASJ AF: 0.0912

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0979 AC: 24502 AN: 250150 Hom.: 1271 AF XY: 0.101 AC XY: 13628 AN XY: 135212

Gnomad AFR exome AF: 0.0980

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0809

Gnomad EAS exome AF: 0.0621

Gnomad SAS exome AF: 0.0995

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.105 AC: 152988 AN: 1458188 Hom.: 8316 Cov.: 32 AF XY: 0.105 AC XY: 76279 AN XY: 725478

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.0595

Gnomad4 ASJ exome AF: 0.0820

Gnomad4 EAS exome AF: 0.0813

Gnomad4 SAS exome AF: 0.0982

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.104 AC: 15719 AN: 151624 Hom.: 818 Cov.: 32 AF XY: 0.105 AC XY: 7748 AN XY: 74088

Gnomad4 AFR AF: 0.0992

Gnomad4 AMR AF: 0.0808

Gnomad4 ASJ AF: 0.0912

Gnomad4 EAS AF: 0.0685

Gnomad4 SAS AF: 0.0900

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.105

Alfa AF: 0.100 Hom.: 1279

Bravo AF: 0.0997

TwinsUK AF: 0.105 AC: 388

ALSPAC AF: 0.114 AC: 439

ESP6500AA AF: 0.0988 AC: 435

ESP6500EA AF: 0.106 AC: 908

ExAC AF: 0.0988 AC: 11990

Asia WGS AF: 0.0640 AC: 220 AN: 3476

EpiCase AF: 0.111

EpiControl AF: 0.113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2018	Variant summary: MUT c.1495G>A (p.Ala499Thr) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.099 in 275710 control chromosomes in the gnomAD database, including 1409 homozygotes. The observed variant frequency is approximately 41-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MUT causing Methylmalonic Acidemia phenotype (0.0024), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2013	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.9
DANN	Benign	0.95
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	-0.25	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.19
Sift	Benign	0.085	T
Sift4G	Benign	0.17	T
Vest4		0.047
MPC		0.088
ClinPred		0.0046	T
GERP RS		-2.1
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229385; hg19: chr6-49415448; COSMIC: COSV51274129;