rs376429075

Positions:

• chr17-17798152-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000353383.6(RAI1):​c.5204C>T​(p.Pro1735Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1735P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RAI1 ENST00000353383.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.508

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17700946).
• BP6: Variant 17-17798152-C-T is Benign according to our data. Variant chr17-17798152-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212011.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr17-17798152-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.5204C>T	p.Pro1735Leu	missense_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.5204C>T	p.Pro1735Leu	missense_variant	3/6	1	NM_030665.4	ENSP00000323074	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249380 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135206

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461136 Hom.: 0 Cov.: 36 AF XY: 0.0000440 AC XY: 32 AN XY: 726890

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74380

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	RAI1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 29, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.92	P;.
Vest4		0.54
MVP		0.093
MPC		0.55
ClinPred		0.48	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.38

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: rs376429075; hg19: chr17-17701466;