dbSNP rs786204847: RIGI:p.Glu373Ala (chr9-32488039-T-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_014314.4(RIGI):c.1118A>C(p.Glu373Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E373D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RIGI
NM_014314.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.41

Publications

28 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), G2P, Ambry Genetics
Singleton-Merten dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RIGI links:

ENSG00000288684 (HGNC:):

ENSG00000288684 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 9-32488039-T-G is Pathogenic according to our data. Variant chr9-32488039-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 189344.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014314.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIGI	NM_014314.4	MANE Select	c.1118A>C	p.Glu373Ala	missense	Exon 8 of 18	NP_055129.2
RIGI	NM_001385907.1		c.1112A>C	p.Glu371Ala	missense	Exon 8 of 18	NP_001372836.1	A0AAQ5BIG4
RIGI	NM_001385913.1		c.1103A>C	p.Glu368Ala	missense	Exon 8 of 18	NP_001372842.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIGI	ENST00000379883.3	TSL:1 MANE Select	c.1118A>C	p.Glu373Ala	missense	Exon 8 of 18	ENSP00000369213.2	O95786-1
ENSG00000288684	ENST00000681750.1		c.968A>C	p.Glu323Ala	missense	Exon 10 of 20	ENSP00000506413.1	A0A7P0TB70
RIGI	ENST00000715271.1		c.1115A>C	p.Glu372Ala	missense	Exon 8 of 18	ENSP00000520440.1	A0AAQ5BIF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Singleton-Merten syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.3

PhyloP100

5.4

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.93

Loss of disorder (P = 0.1115)

MVP

0.98

MPC

0.55

ClinPred

1.0

GERP RS

4.6

Varity_R

0.98

gMVP

0.85

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over