9-32492531-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014314.4(RIGI):c.431C>G(p.Ser144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S144P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RIGI
NM_014314.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.313

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16855577).

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
RIGI	NM_014314.4	MANE Select	c.431C>G	p.Ser144Cys	missense	Exon 4 of 18	NP_055129.2
RIGI	NM_001385910.1		c.-11C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001372839.1
RIGI	NM_001385914.1		c.-11C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001372843.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIGI	ENST00000379883.3	TSL:1 MANE Select	c.431C>G	p.Ser144Cys	missense	Exon 4 of 18	ENSP00000369213.2
ENSG00000288684	ENST00000681750.1		c.281C>G	p.Ser94Cys	missense	Exon 6 of 20	ENSP00000506413.1
RIGI	ENST00000715271.1		c.428C>G	p.Ser143Cys	missense	Exon 4 of 18	ENSP00000520440.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727218

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.8

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.48

M_CAP

Benign

0.012

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

-0.31

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.072

Sift

Benign

0.061

Sift4G

Uncertain

0.027

Polyphen

0.98

Vest4

0.099

MutPred

0.34

Gain of helix (P = 0.062)

MVP

0.45

MPC

0.27

ClinPred

0.14

GERP RS

-2.0

Varity_R

0.18

gMVP

0.24

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over