rs771542321

chr6-49451464-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1_Strong PM2 PP3 PP5_Very_Strong

The NM_000255.4(MMUT):c.1332+1del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MMUT NM_000255.4 splice_donor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 15 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.11007545 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.7, offset of 0 (no position change), new splice context is: aaaGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-49451464-AC-A is Pathogenic according to our data. Variant chr6-49451464-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 554656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.1332+1del		splice_donor_variant		ENST00000274813.4
MMUT	XM_005249143.4	c.1332+1del		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1332+1del		splice_donor_variant		1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250792 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change creates a premature translational stop signal (Splice site) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs771542321, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286). This variant is also known as c.1332+1delG. ClinVar contains an entry for this variant (Variation ID: 554656). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26672496, 27233228, 25959030, 32754920, 16281286, 21048060) -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: 3
DS_DL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771542321; hg19: chr6-49419177;