17-17793217-G-T

Variant names:

• chr17-17793217-G-T
• rs3803763
• NM_030665.4:c.269G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_030665.4(RAI1):​c.269G>T​(p.Gly90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. G90A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.227
• Publications: 0 publications found

Genes affected

RAI1 (HGNC:9834): (retinoic acid induced 1) This gene is located within the Smith-Magenis syndrome region on chromosome 17. It is highly similar to its mouse counterpart and is expressed at high levels mainly in neuronal tissues. The protein encoded by this gene includes a polymorphic polyglutamine tract in the N-terminal domain. Expression of the mouse counterpart in neurons is induced by retinoic acid. This gene is associated with both the severity of the phenotype and the response to medication in schizophrenic patients. [provided by RefSeq, Jul 2008]

RAI1 Gene-Disease associations (from GenCC):

• Smith-Magenis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Potocki-Lupski syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05183792).
• BP6: Variant 17-17793217-G-T is Benign according to our data. Variant chr17-17793217-G-T is described in ClinVar as Benign. ClinVar VariationId is 2021308.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	NM_030665.4	MANE Select	c.269G>T	p.Gly90Val	missense	Exon 3 of 6	NP_109590.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	ENST00000353383.6	TSL:1 MANE Select	c.269G>T	p.Gly90Val	missense	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.269G>T	p.Gly90Val	missense	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.269G>T	p.Gly90Val	missense	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459384 Hom.: 0 Cov.: 84 AF XY: 0.00000138 AC XY: 1 AN XY: 725880

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111136

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.8
DANN	Benign	0.69
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.23
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.11
Sift	Uncertain	0.028	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.18		Loss of loop (P = 0.0374)
MVP		0.19
MPC		0.33
ClinPred		0.16	T
GERP RS		1.1
Varity_R		0.047
gMVP		0.13
Mutation Taster		=100/0	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: rs3803763; hg19: chr17-17696531;