6-49443906-A-G

Position:

• chr6-49443906-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1676+733T>C		intron_variant		ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1676+733T>C		intron_variant			XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1676+733T>C		intron_variant		1	NM_000255.4	ENSP00000274813	P1

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

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.356

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.334

Alfa AF: 0.366 Hom.: 4765

Bravo AF: 0.352

Asia WGS AF: 0.342 AC: 1193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.6
DANN	Benign	0.70

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