rs138332224

chr17-17793558-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):c.610C>T(p.Pro204Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,912 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (10 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005404234).
• BP6: Variant 17-17793558-C-T is Benign according to our data. Variant chr17-17793558-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793558-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (365/152286) while in subpopulation NFE AF= 0.00228 (155/67990). AF 95% confidence interval is 0.00199. There are 2 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.610C>T	p.Pro204Ser	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.610C>T	p.Pro204Ser	missense_variant	3/6	1	NM_030665.4	P1
RAI1	ENST00000395774.1	c.610C>T	p.Pro204Ser	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00261 AC: 655 AN: 251070 Hom.: 5 AF XY: 0.00250 AC XY: 340 AN XY: 135794

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00166 AC: 2429 AN: 1461626 Hom.: 10 Cov.: 97 AF XY: 0.00168 AC XY: 1218 AN XY: 727112

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00222 AC: 269

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RAI1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 10, 2018

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RAI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	6.2
Dann	Benign	0.85
DEOGEN2	Benign	0.087	T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	N;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.034
Sift	Benign	0.50	T;T;.
Sift4G	Benign	0.87	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.18
MVP		0.13
MPC		0.27
ClinPred		0.0054	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.045
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs138332224; hg19: chr17-17696872;