6-49431526-A-AT

Variant names:

• chr6-49431526-A-AT
• rs10713340
• NM_000255.4:c.*201dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000255.4(MMUT):​c.*201dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (82 hom., cov: 0)
  • Exomes 𝑓: 0.0051 (9 hom.)
• Consequence: MMUT NM_000255.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 6-49431526-A-AT is Benign according to our data. Variant chr6-49431526-A-AT is described in ClinVar as [Benign]. Clinvar id is 1227019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.*201dupA		3_prime_UTR_variant	Exon 13 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.*201dupA		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.*201dupA		3_prime_UTR_variant	Exon 13 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3020 AN: 150536 Hom.: 82 Cov.: 0

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.0126

GnomAD4 exome AF: 0.00510 AC: 1571 AN: 307790 Hom.: 9 Cov.: 0 AF XY: 0.00471 AC XY: 771 AN XY: 163780

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0660 AC: 584 AN: 8844

American (AMR) AF: 0.00864 AC: 105 AN: 12152

Ashkenazi Jewish (ASJ) AF: 0.00732 AC: 65 AN: 8876

East Asian (EAS) AF: 0.00238 AC: 46 AN: 19346

South Asian (SAS) AF: 0.00148 AC: 50 AN: 33860

European-Finnish (FIN) AF: 0.00139 AC: 32 AN: 22956

Middle Eastern (MID) AF: 0.0117 AC: 15 AN: 1278

European-Non Finnish (NFE) AF: 0.00289 AC: 531 AN: 183718

Other (OTH) AF: 0.00853 AC: 143 AN: 16760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0201 AC: 3024 AN: 150646 Hom.: 82 Cov.: 0 AF XY: 0.0191 AC XY: 1402 AN XY: 73518

African (AFR) AF: 0.0660 AC: 2713 AN: 41132

American (AMR) AF: 0.00936 AC: 141 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3464

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5106

South Asian (SAS) AF: 0.000842 AC: 4 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10272

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00181 AC: 122 AN: 67574

Other (OTH) AF: 0.0125 AC: 26 AN: 2086

Alfa AF: 0.000108 Hom.: 346

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism

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: rs10713340; hg19: chr6-49399239;