rs11649804

chr17-17793441-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030665.4(RAI1):c.493C>A(p.Pro165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,504 control chromosomes in the GnomAD database, including 115,868 homozygotes. In-silico tool predicts 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. P165R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (11981 hom., cov: 32)
  • Exomes 𝑓: 0.35 (103887 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.710

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=8.54322E-7).
• BP6: Variant 17-17793441-C-A is Benign according to our data. Variant chr17-17793441-C-A is described in ClinVar as [Benign]. Clinvar id is 96194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793441-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.493C>A	p.Pro165Thr	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.493C>A	p.Pro165Thr	missense_variant	3/6	1	NM_030665.4	P1
RAI1	ENST00000395774.1	c.493C>A	p.Pro165Thr	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57083 AN: 151868 Hom.: 11979 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.443 AC: 111013 AN: 250752 Hom.: 29243 AF XY: 0.447 AC XY: 60621 AN XY: 135702

Gnomad AFR exome AF: 0.393

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.852

Gnomad SAS exome AF: 0.718

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.350 AC: 511481 AN: 1461518 Hom.: 103887 Cov.: 86 AF XY: 0.360 AC XY: 261888 AN XY: 727064

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.569

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.713

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.376 AC: 57111 AN: 151986 Hom.: 11981 Cov.: 32 AF XY: 0.388 AC XY: 28833 AN XY: 74268

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.466

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.845

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.364

Alfa AF: 0.332 Hom.: 22191

Bravo AF: 0.383

TwinsUK AF: 0.287 AC: 1064

ALSPAC AF: 0.297 AC: 1144

ESP6500AA AF: 0.395 AC: 1742

ESP6500EA AF: 0.307 AC: 2643

ExAC AF: 0.439 AC: 53335

Asia WGS AF: 0.703 AC: 2441 AN: 3476

EpiCase AF: 0.312

EpiControl AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Smith-Magenis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	8.5e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.75	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;D;.
REVEL	Benign	0.079
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.039	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.19
MPC		0.77
ClinPred		0.046	T
GERP RS		3.6
Varity_R		0.31
gMVP		0.26

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: rs11649804; hg19: chr17-17696755; COSMIC: COSV55389022; COSMIC: COSV55389022;