rs34898721

Positions:

• chr17-17794227-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000353383.6(RAI1):​c.1279C>T​(p.Leu427=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,462 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: RAI1 ENST00000353383.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.98

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-17794227-C-T is Benign according to our data. Variant chr17-17794227-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17794227-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (159/152358) while in subpopulation NFE AF= 0.00175 (119/68036). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.1279C>T	p.Leu427=	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.1279C>T	p.Leu427=	synonymous_variant	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.1279C>T	p.Leu427=	synonymous_variant	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000975 AC: 244 AN: 250378 Hom.: 0 AF XY: 0.00106 AC XY: 143 AN XY: 135538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00105 AC: 1536 AN: 1461104 Hom.: 2 Cov.: 94 AF XY: 0.00107 AC XY: 777 AN XY: 726850

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000872 AC XY: 65 AN XY: 74512

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000907

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RAI1: BP4, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2016

This alteration is classified as likely 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	-0.42
CADD	Benign	7.3
DANN	Benign	0.73

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: rs34898721; hg19: chr17-17697541;