19-13764607-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001031727.4(MRI1):c.19C>T(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,609,452 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (38 hom.)
• Consequence: MRI1 NM_001031727.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010465771).
• BP6: Variant 19-13764607-C-T is Benign according to our data. Variant chr19-13764607-C-T is described in ClinVar as [Benign]. Clinvar id is 720597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1946/152136) while in subpopulation AFR AF= 0.043 (1786/41510). AF 95% confidence interval is 0.0414. There are 32 homozygotes in gnomad4. There are 914 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRI1	NM_001031727.4	c.19C>T	p.Arg7Cys	missense_variant	1/6	ENST00000040663.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRI1	ENST00000040663.8	c.19C>T	p.Arg7Cys	missense_variant	1/6	1	NM_001031727.4	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1946 AN: 152020 Hom.: 32 Cov.: 30

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00424 AC: 1032 AN: 243560 Hom.: 23 AF XY: 0.00320 AC XY: 425 AN XY: 132984

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.00566

GnomAD4 exome AF: 0.00166 AC: 2425 AN: 1457316 Hom.: 38 Cov.: 30 AF XY: 0.00148 AC XY: 1073 AN XY: 725112

Gnomad4 AFR exome AF: 0.0432

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.00985

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.0128 AC: 1946 AN: 152136 Hom.: 32 Cov.: 30 AF XY: 0.0123 AC XY: 914 AN XY: 74390

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00303 Hom.: 12

Bravo AF: 0.0149

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.000816 AC: 7

ExAC AF: 0.00469 AC: 568

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.21
Sift	Benign	0.12	T;T
Sift4G	Benign	0.095	T;T
Polyphen		0.078	B;B
Vest4		0.72
MVP		0.50
MPC		0.32
ClinPred		0.059	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.62
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs79169978; hg19: chr19-13875421;