rs61746214

chr17-17796739-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):c.3791A>G(p.Glu1264Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00125 in 1,613,466 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (14 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.17

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=0.005512506).
• BP6: Variant 17-17796739-A-G is Benign according to our data. Variant chr17-17796739-A-G is described in ClinVar as [Benign]. Clinvar id is 130087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17796739-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00657 (1000/152270) while in subpopulation AFR AF= 0.023 (957/41558). AF 95% confidence interval is 0.0218. There are 7 homozygotes in gnomad4. There are 469 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 999 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.3791A>G	p.Glu1264Gly	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.3791A>G	p.Glu1264Gly	missense_variant	3/6	1	NM_030665.4	P1

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 999 AN: 152152 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00173 AC: 433 AN: 250710 Hom.: 5 AF XY: 0.00120 AC XY: 163 AN XY: 135602

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000699 AC: 1021 AN: 1461196 Hom.: 14 Cov.: 37 AF XY: 0.000600 AC XY: 436 AN XY: 726878

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00657 AC: 1000 AN: 152270 Hom.: 7 Cov.: 33 AF XY: 0.00630 AC XY: 469 AN XY: 74448

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00166 Hom.: 3

Bravo AF: 0.00811

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.81	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.11	T;.
Polyphen		1.0	D;.
Vest4		0.41
MVP		0.48
MPC		0.40
ClinPred		0.054	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.28

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: rs61746214; hg19: chr17-17700053; COSMIC: COSV55400062; COSMIC: COSV55400062;