rs549244691

Positions:

• chr17-17794798-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030665.4(RAI1):​c.1850C>A​(p.Ala617Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,136 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.02

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018631965).
• BP6: Variant 17-17794798-C-A is Benign according to our data. Variant chr17-17794798-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196546.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000116 (169/1460832) while in subpopulation SAS AF= 0.00168 (145/86256). AF 95% confidence interval is 0.00146. There are 2 homozygotes in gnomad4_exome. There are 113 alleles in male gnomad4_exome subpopulation. Median coverage is 94. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.1850C>A	p.Ala617Asp	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.1850C>A	p.Ala617Asp	missense_variant	3/6	1	NM_030665.4	P1
RAI1	ENST00000395774.1	c.1850C>A	p.Ala617Asp	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000268 AC: 67 AN: 249646 Hom.: 2 AF XY: 0.000354 AC XY: 48 AN XY: 135500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1460832 Hom.: 2 Cov.: 94 AF XY: 0.000155 AC XY: 113 AN XY: 726748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2014	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;D;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.63
MutPred		0.15		Gain of disorder (P = 0.0975);Gain of disorder (P = 0.0975);.;
MVP		0.47
MPC		1.2
ClinPred		0.095	T
GERP RS		5.4
Varity_R		0.61
gMVP		0.35

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: rs549244691; hg19: chr17-17698112; COSMIC: COSV55395219; COSMIC: COSV55395219;