19-13765097-CGGTCCGGGAGA-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001031727.4(MRI1):c.363_371+2del variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,539,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: MRI1 NM_001031727.4 frameshift, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.19

Genes affected

MRI1 (HGNC:28469): (methylthioribose-1-phosphate isomerase 1) This enzyme functions in the methionine salvage pathway by catalyzing the interconversion of methylthioribose-1-phosphate and methythioribulose-1-phosphate. Elevated expression of the encoded protein is associated with metastatic melanoma and this protein promotes melanoma cell invasion independent of its enzymatic activity. Mutations in this gene may be associated with vanishing white matter disease (VMWD). [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRI1	NM_001031727.4	c.363_371+2del		frameshift_variant, splice_region_variant	2/6	ENST00000040663.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRI1	ENST00000040663.8	c.363_371+2del		frameshift_variant, splice_region_variant	2/6	1	NM_001031727.4	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.000750

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000348 AC: 57 AN: 163946 Hom.: 0 AF XY: 0.000366 AC XY: 33 AN XY: 90166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000276

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: 0.000633

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.000648 AC: 899 AN: 1386808 Hom.: 0 AF XY: 0.000617 AC XY: 424 AN XY: 686794

Gnomad4 AFR exome AF: 0.0000330

Gnomad4 AMR exome AF: 0.000406

Gnomad4 ASJ exome AF: 0.0000408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000520

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152312 Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 36 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000565 Hom.: 0

Bravo AF: 0.000548

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 29, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs747238951; hg19: chr19-13875911;