19-13764977-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031727.4(MRI1):c.239G>T(p.Arg80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MRI1 NM_001031727.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30920488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRI1	NM_001031727.4	c.239G>T	p.Arg80Leu	missense_variant	2/6	ENST00000040663.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRI1	ENST00000040663.8	c.239G>T	p.Arg80Leu	missense_variant	2/6	1	NM_001031727.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365268 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 673432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000407

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.239G>T (p.R80L) alteration is located in exon 2 (coding exon 2) of the MRI1 gene. This alteration results from a G to T substitution at nucleotide position 239, causing the arginine (R) at amino acid position 80 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	18
Dann	Benign	0.80
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.26	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.71	P;B
Vest4		0.37
MutPred		0.73		Loss of MoRF binding (P = 0.0164);Loss of MoRF binding (P = 0.0164);
MVP		0.65
MPC		0.30
ClinPred		0.67	D
GERP RS		0.56
Varity_R		0.34
gMVP		0.55

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13875791;