6-49431148-T-C

Variant names:

• chr6-49431148-T-C
• rs11757098
• NM_000255.4:c.*580A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000255.4(MMUT):​c.*580A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,286 control chromosomes in the GnomAD database, including 1,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1130 hom., cov: 32)
  • Exomes 𝑓: 0.098 (1 hom.)
• Consequence: MMUT NM_000255.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-49431148-T-C is Benign according to our data. Variant chr6-49431148-T-C is described in ClinVar as Benign. ClinVar VariationId is 357242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 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.*580A>G		3_prime_UTR	Exon 13 of 13	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.*580A>G		3_prime_UTR	Exon 13 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.*580A>G		3_prime_UTR	Exon 13 of 13	ENSP00000548119.1
	MMUT	ENST00000953754.1		c.*580A>G		3_prime_UTR	Exon 14 of 14	ENSP00000623813.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16511 AN: 152046 Hom.: 1130 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0881

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0984 AC: 12 AN: 122 Hom.: 1 Cov.: 0 AF XY: 0.0682 AC XY: 6 AN XY: 88

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0714 AC: 1 AN: 14

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.102 AC: 10 AN: 98

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.108 AC: 16509 AN: 152164 Hom.: 1130 Cov.: 32 AF XY: 0.106 AC XY: 7919 AN XY: 74410

African (AFR) AF: 0.0392 AC: 1629 AN: 41540

American (AMR) AF: 0.0884 AC: 1350 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3470

East Asian (EAS) AF: 0.172 AC: 888 AN: 5174

South Asian (SAS) AF: 0.187 AC: 903 AN: 4822

European-Finnish (FIN) AF: 0.0881 AC: 933 AN: 10586

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10069 AN: 67978

Other (OTH) AF: 0.109 AC: 231 AN: 2110

Alfa AF: 0.122 Hom.: 469

Bravo AF: 0.102

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.25
DANN	Benign	0.61
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs11757098; hg19: chr6-49398861; COSMIC: COSV51281188;