NM_014314.4:c.2367C>A

Variant names:

• chr9-32459485-G-T
• rs35253851
• NM_014314.4:c.2367C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014314.4(RIGI):​c.2367C>A​(p.Phe789Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIGI NM_014314.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.795
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01414147).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIGI	NM_014314.4	MANE Select	c.2367C>A	p.Phe789Leu	missense	Exon 17 of 18	NP_055129.2
	RIGI	NM_001385907.1		c.2361C>A	p.Phe787Leu	missense	Exon 17 of 18	NP_001372836.1
	RIGI	NM_001385913.1		c.2352C>A	p.Phe784Leu	missense	Exon 17 of 18	NP_001372842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIGI	ENST00000379883.3	TSL:1 MANE Select	c.2367C>A	p.Phe789Leu	missense	Exon 17 of 18	ENSP00000369213.2
	ENSG00000288684	ENST00000681750.1		c.2217C>A	p.Phe739Leu	missense	Exon 19 of 20	ENSP00000506413.1
	RIGI	ENST00000715271.1		c.2364C>A	p.Phe788Leu	missense	Exon 17 of 18	ENSP00000520440.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248954 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459812 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726328

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111656

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000173 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.31
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.80
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.0090
Sift	Benign	0.66	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.37		Loss of methylation at K788 (P = 0.0448)
MVP		0.27
MPC		0.13
ClinPred		0.047	T
GERP RS		-0.40
Varity_R		0.13
gMVP		0.15
Mutation Taster		=88/12	polymorphism

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: rs35253851; hg19: chr9-32459483;