6-49431471-T-G

Variant names:

• chr6-49431471-T-G
• rs187747098
• NM_000255.4:c.*257A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000255.4(MMUT):​c.*257A>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 0.00189 in 247,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: MMUT NM_000255.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (336/152186) while in subpopulation AFR AF = 0.00457 (190/41550). AF 95% confidence interval is 0.00404. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.*257A>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.*257A>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.*257A>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152072 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00137 AC: 131 AN: 95432 Hom.: 0 Cov.: 0 AF XY: 0.00126 AC XY: 63 AN XY: 49878

African (AFR) AF: 0.00504 AC: 13 AN: 2578

American (AMR) AF: 0.00114 AC: 5 AN: 4386

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 78 AN: 3300

East Asian (EAS) AF: 0.00 AC: 0 AN: 6428

South Asian (SAS) AF: 0.000118 AC: 1 AN: 8486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 388

European-Non Finnish (NFE) AF: 0.000289 AC: 17 AN: 58736

Other (OTH) AF: 0.00301 AC: 17 AN: 5640

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152186 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74398

African (AFR) AF: 0.00457 AC: 190 AN: 41550

American (AMR) AF: 0.00203 AC: 31 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.64
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs187747098; hg19: chr6-49399184;