6-49443906-A-G

Variant names:

• chr6-49443906-A-G
• rs6458690
• NM_000255.4:c.1676+733T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000255.4(MMUT):​c.1676+733T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 342,034 control chromosomes in the GnomAD database, including 22,848 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10225 hom., cov: 31)
  • Exomes 𝑓: 0.37 (12623 hom.)
• Consequence: MMUT NM_000255.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.771
• Publications: 16 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: Labcorp Genetics (formerly Invitae), ClinGen, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.1676+733T>C		intron	N/A	NP_000246.2	P22033

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.1676+733T>C		intron	N/A	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.1676+733T>C		intron	N/A	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.1676+733T>C		intron	N/A	ENSP00000548121.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55111 AN: 151774 Hom.: 10211 Cov.: 31

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.369 AC: 70189 AN: 190142 Hom.: 12623 AF XY: 0.370 AC XY: 41607 AN XY: 112466

African (AFR) AF: 0.444 AC: 1723 AN: 3878

American (AMR) AF: 0.245 AC: 2991 AN: 12204

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 2263 AN: 6356

East Asian (EAS) AF: 0.249 AC: 1319 AN: 5290

South Asian (SAS) AF: 0.369 AC: 14868 AN: 40324

European-Finnish (FIN) AF: 0.391 AC: 3147 AN: 8056

Middle Eastern (MID) AF: 0.276 AC: 634 AN: 2294

European-Non Finnish (NFE) AF: 0.388 AC: 39964 AN: 102982

Other (OTH) AF: 0.375 AC: 3280 AN: 8758

GnomAD4 genome AF: 0.363 AC: 55158 AN: 151892 Hom.: 10225 Cov.: 31 AF XY: 0.360 AC XY: 26688 AN XY: 74214

African (AFR) AF: 0.411 AC: 17021 AN: 41420

American (AMR) AF: 0.260 AC: 3961 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1131 AN: 5148

South Asian (SAS) AF: 0.372 AC: 1790 AN: 4814

European-Finnish (FIN) AF: 0.372 AC: 3929 AN: 10562

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25051 AN: 67920

Other (OTH) AF: 0.334 AC: 703 AN: 2106

Alfa AF: 0.365 Hom.: 5339

Bravo AF: 0.352

Asia WGS AF: 0.342 AC: 1193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.6
DANN	Benign	0.70
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6458690; hg19: chr6-49411619; COSMIC: COSV51272691;