9-32480253-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014314.4(RIGI):c.1740T>A(p.Asp580Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,609,856 control chromosomes in the GnomAD database, including 14,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D580N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 999 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13152 hom. )

Consequence

RIGI
NM_014314.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.01

Publications

38 publications found

Variant links:

Genes affected

RIGI (HGNC:19102): (RNA sensor RIG-I) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular processes involving RNA binding and alteration of RNA secondary structure. This gene encodes a protein containing RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD). It is involved in viral double-stranded (ds) RNA recognition and the regulation of the antiviral innate immune response. Mutations in this gene are associated with Singleton-Merten syndrome 2. [provided by RefSeq, Aug 2020]

RIGI Gene-Disease associations (from GenCC):

Singleton-Merten syndrome 2
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Singleton-Merten dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RIGI links:

ENSG00000288684 (HGNC:):

ENSG00000288684 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015563965).

BP6

Variant 9-32480253-A-T is Benign according to our data. Variant chr9-32480253-A-T is described in ClinVar as Benign. ClinVar VariationId is 1168118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIGI	NM_014314.4 link	c.1740T>A	p.Asp580Glu	missense_variant	Exon 12 of 18	ENST00000379883.3	NP_055129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIGI	ENST00000379883.3 link	c.1740T>A	p.Asp580Glu	missense_variant	Exon 12 of 18	1	NM_014314.4	ENSP00000369213.2
ENSG00000288684	ENST00000681750.1 link	c.1590T>A	p.Asp530Glu	missense_variant	Exon 14 of 20			ENSP00000506413.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15586

AN:

152134

Hom.:

1000

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.178

Gnomad AMR

AF:

0.0878

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.0133

Gnomad SAS

AF:

0.0629

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.109

AC:

27302

AN:

251010

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0255

Gnomad AMR exome

AF:

0.0585

Gnomad ASJ exome

AF:

0.207

Gnomad EAS exome

AF:

0.00881

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.149

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.129

AC:

187427

AN:

1457604

Hom.:

13152

Cov.:

AF XY:

0.128

AC XY:

92725

AN XY:

724696

show subpopulations

African (AFR)

AF:

0.0279

AC:

933

AN:

33460

American (AMR)

AF:

0.0634

AC:

2831

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

5425

AN:

26028

East Asian (EAS)

AF:

0.00974

AC:

386

AN:

39614

South Asian (SAS)

AF:

0.0668

AC:

5732

AN:

85850

European-Finnish (FIN)

AF:

0.138

AC:

7366

AN:

53304

Middle Eastern (MID)

AF:

0.216

AC:

1245

AN:

5752

European-Non Finnish (NFE)

AF:

0.141

AC:

155972

AN:

1108734

Other (OTH)

AF:

0.125

AC:

7537

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

8031

16061

24092

32122

40153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5366

10732

16098

21464

26830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15582

AN:

152252

Hom.:

999

Cov.:

AF XY:

0.100

AC XY:

7451

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0309

AC:

1282

AN:

41540

American (AMR)

AF:

0.0877

AC:

1341

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

718

AN:

3468

East Asian (EAS)

AF:

0.0133

AC:

AN:

5188

South Asian (SAS)

AF:

0.0628

AC:

303

AN:

4826

European-Finnish (FIN)

AF:

0.136

AC:

1444

AN:

10596

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.146

AC:

9918

AN:

68020

Other (OTH)

AF:

0.124

AC:

261

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

721

1442

2163

2884

3605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.123

Hom.:

475

Bravo

AF:

0.0964

TwinsUK

AF:

0.129

AC:

478

ALSPAC

AF:

0.142

AC:

549

ESP6500AA

AF:

0.0322

AC:

142

ESP6500EA

AF:

0.147

AC:

1268

ExAC

AF:

0.111

AC:

13445

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported.

Singleton-Merten syndrome 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;M

PhyloP100

2.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.090

Sift

Benign

0.056

T;T

Sift4G

Uncertain

0.025

D;D

Vest4

0.092

ClinPred

0.030

GERP RS

4.7

Varity_R

0.26

gMVP

0.27

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over