rs141757356

chr17-17795855-C-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.2907C>T(p.Asp969=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,106 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (5 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.48

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=-0.91).
• BP6: Variant 17-17795855-C-T is Benign according to our data. Variant chr17-17795855-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17795855-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00447 (681/152312) while in subpopulation AFR AF= 0.0139 (577/41578). AF 95% confidence interval is 0.0129. There are 3 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 680 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.2907C>T	p.Asp969=	synonymous_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.2907C>T	p.Asp969=	synonymous_variant	3/6	1	NM_030665.4	P1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152194 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00166 AC: 414 AN: 250062 Hom.: 3 AF XY: 0.00128 AC XY: 173 AN XY: 135428

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000593

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.000819 AC: 1197 AN: 1460794 Hom.: 5 Cov.: 37 AF XY: 0.000786 AC XY: 571 AN XY: 726702

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000382

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00447 AC: 681 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00436 AC XY: 325 AN XY: 74484

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00238 Hom.: 1

Bravo AF: 0.00508

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2019	This variant is associated with the following publications: (PMID: 21857958) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	RAI1: BP4, BP7, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.24
Dann	Benign	0.56

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: rs141757356; hg19: chr17-17699169; COSMIC: COSV55391506; COSMIC: COSV55391506;