NM_014314.4:c.691+59G>A

Variant names:

• chr9-32491242-C-T
• rs6476363
• NM_014314.4:c.691+59G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014314.4(RIGI):​c.691+59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,580,764 control chromosomes in the GnomAD database, including 235,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (18462 hom., cov: 31)
  • Exomes 𝑓: 0.54 (216626 hom.)
• Consequence: RIGI NM_014314.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0400
• Publications: 17 publications found

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

ENSG00000288684 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-32491242-C-T is Benign according to our data. Variant chr9-32491242-C-T is described in ClinVar as Benign. ClinVar VariationId is 2637874.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIGI	NM_014314.4	c.691+59G>A		intron_variant	Intron 5 of 17	ENST00000379883.3	NP_055129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIGI	ENST00000379883.3	c.691+59G>A		intron_variant	Intron 5 of 17	1	NM_014314.4	ENSP00000369213.2
ENSG00000288684	ENST00000681750.1	c.541+59G>A		intron_variant	Intron 7 of 19			ENSP00000506413.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73256 AN: 151732 Hom.: 18465 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.513

GnomAD4 exome AF: 0.544 AC: 777190 AN: 1428914 Hom.: 216626 AF XY: 0.546 AC XY: 387984 AN XY: 710764

African (AFR) AF: 0.357 AC: 11256 AN: 31544

American (AMR) AF: 0.386 AC: 13719 AN: 35584

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 15475 AN: 25208

East Asian (EAS) AF: 0.167 AC: 6468 AN: 38738

South Asian (SAS) AF: 0.533 AC: 42318 AN: 79350

European-Finnish (FIN) AF: 0.472 AC: 24642 AN: 52222

Middle Eastern (MID) AF: 0.617 AC: 3512 AN: 5692

European-Non Finnish (NFE) AF: 0.571 AC: 628518 AN: 1101462

Other (OTH) AF: 0.529 AC: 31282 AN: 59114

GnomAD4 genome AF: 0.483 AC: 73274 AN: 151850 Hom.: 18462 Cov.: 31 AF XY: 0.475 AC XY: 35260 AN XY: 74196

African (AFR) AF: 0.365 AC: 15107 AN: 41416

American (AMR) AF: 0.445 AC: 6777 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2071 AN: 3458

East Asian (EAS) AF: 0.198 AC: 1020 AN: 5152

South Asian (SAS) AF: 0.539 AC: 2585 AN: 4796

European-Finnish (FIN) AF: 0.461 AC: 4856 AN: 10532

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39042 AN: 67942

Other (OTH) AF: 0.509 AC: 1074 AN: 2108

Alfa AF: 0.554 Hom.: 12060

Bravo AF: 0.473

Asia WGS AF: 0.380 AC: 1323 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 14, 2023

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 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.1
DANN	Benign	0.20
PhyloP100		0.040
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6476363; hg19: chr9-32491240; COSMIC: COSV65882136;