rs4925112

Positions:

• chr17-17797259-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030665.4(RAI1):​c.4311T>C​(p.Pro1437Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,612,960 control chromosomes in the GnomAD database, including 5,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1534 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3553 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.11

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 17-17797259-T-C is Benign according to our data. Variant chr17-17797259-T-C is described in ClinVar as [Benign]. Clinvar id is 96190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17797259-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.4311T>C	p.Pro1437Pro	synonymous_variant	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.4311T>C	p.Pro1437Pro	synonymous_variant	3/6	1	NM_030665.4	ENSP00000323074.4

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16435 AN: 151972 Hom.: 1522 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0943

GnomAD3 exomes AF: 0.0605 AC: 15096 AN: 249448 Hom.: 882 AF XY: 0.0568 AC XY: 7691 AN XY: 135360

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00285

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0783

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0606 AC: 88581 AN: 1460870 Hom.: 3553 Cov.: 37 AF XY: 0.0587 AC XY: 42660 AN XY: 726728

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0386

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0270

Gnomad4 FIN exome AF: 0.0763

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0645

GnomAD4 genome AF: 0.108 AC: 16486 AN: 152090 Hom.: 1534 Cov.: 33 AF XY: 0.107 AC XY: 7927 AN XY: 74358

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.0565

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.0246

Gnomad4 FIN AF: 0.0748

Gnomad4 NFE AF: 0.0596

Gnomad4 OTH AF: 0.0986

Alfa AF: 0.0653 Hom.: 520

Bravo AF: 0.114

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 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. -

Smith-Magenis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.035
DANN	Benign	0.33

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: rs4925112; hg19: chr17-17700573;