rs117995220

chr17-17797460-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_030665.4(RAI1):c.4512G>T(p.Leu1504=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,613,362 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (40 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.43

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=-0.5).
• BP6: Variant 17-17797460-G-T is Benign according to our data. Variant chr17-17797460-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 96191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17797460-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00545 (830/152170) while in subpopulation AMR AF= 0.00895 (137/15302). AF 95% confidence interval is 0.00773. There are 3 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 830 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.4512G>T	p.Leu1504=	synonymous_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.4512G>T	p.Leu1504=	synonymous_variant	3/6	1	NM_030665.4	P1

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 830 AN: 152052 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00574 AC: 1431 AN: 249324 Hom.: 8 AF XY: 0.00603 AC XY: 816 AN XY: 135336

Gnomad AFR exome AF: 0.000888

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00806

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00662 AC: 9667 AN: 1461192 Hom.: 40 Cov.: 37 AF XY: 0.00647 AC XY: 4705 AN XY: 726886

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00705

Gnomad4 NFE exome AF: 0.00738

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.00545 AC: 830 AN: 152170 Hom.: 3 Cov.: 33 AF XY: 0.00560 AC XY: 417 AN XY: 74410

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00895

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00660

Gnomad4 NFE AF: 0.00746

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00731 Hom.: 4

Bravo AF: 0.00608

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RAI1: BP4, BS1, BS2 -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

Smith-Magenis syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 10, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

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
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.5
Dann	Benign	0.76

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: rs117995220; hg19: chr17-17700774;