1-181049076-G-A

Position:

chr1-181049076-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBS2_Supporting

The NM_001385161.1(MR1):c.92G>A(p.Arg31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,946 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0074 ( 9 hom., cov: 33)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

MR1
NM_001385161.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: -0.270

Variant links:

Genes affected

MR1 (HGNC:4975): (major histocompatibility complex, class I-related) MAIT (mucosal-associated invariant T-cells) lymphocytes represent a small population of T-cells primarily found in the gut. The protein encoded by this gene is an antigen-presenting molecule that presents metabolites of microbial vitamin B to MAITs. This presentation may activate the MAITs to regulate the amounts of specific types of bacteria in the gut. Several transcript variants encoding different isoforms have been found for this gene, and a pseudogene of it has been detected about 36 kbp upstream on the same chromosome. [provided by RefSeq, Jul 2015]

MR1 links:

MR1 (HGNC:):

MR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005271584).

BP6

Variant 1-181049076-G-A is Benign according to our data. Variant chr1-181049076-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 996147.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 1127 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MR1	NM_001385161.1 linkuse as main transcript	c.92G>A	p.Arg31His	missense_variant	2/6	ENST00000367580.6	NP_001372090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MR1	ENST00000367580.6 linkuse as main transcript	c.92G>A	p.Arg31His	missense_variant	2/6	1	NM_001385161.1	ENSP00000356552.5		Q95460-1

Frequencies

GnomAD3 genomes

AF:

0.00740

AC:

1126

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00750

AC:

1882

AN:

250934

Hom.:

AF XY:

0.00741

AC XY:

1005

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00504

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00670

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00915

GnomAD4 exome

AF:

0.0110

AC:

16010

AN:

1461622

Hom.:

110

Cov.:

AF XY:

0.0107

AC XY:

7780

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00485

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00695

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.00802

GnomAD4 genome

AF:

0.00740

AC:

1127

AN:

152324

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

526

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00705

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00769

AC:

934

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0114

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro;research

Rossjohn lab, Monash University

The R31H variant in MR1 has been reported in 1 family with autosomal recessive inheritance of mild primary immunodeficiency characterised by persistent HPV warts as well as difficult to treat bacterial and viral infections. Protein structure and function studies of this variant shows disruption of antigen binding, preventing antigen presentation via MR1. This disrupts the development/maintenance of mucosal-associated invariant T (MAIT) cells. Thus we consider this variant is pathogenic but requires characterisation of more individuals with this variant to confirm penetrance of clinical symptoms. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

MR1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.028

.;T;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.76

T;T;T;T;.;.

MetaRNN

Benign

0.0053

T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

-0.39

N;N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.65

.;.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.25

.;.;T;T;T;T

Sift4G

Benign

0.53

T;T;T;T;T;T

Polyphen

1.0

D;D;.;D;D;D

Vest4

0.13

MVP

0.41

MPC

0.26

ClinPred

0.050

GERP RS

-9.6

Varity_R

0.37

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over