rs766951273

Variant names:

• chr1-8359916-C-A
• rs766951273
• NM_001042681.2:c.3466G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-8359916-C-A
• chr1-8359916-C-G
• chr1-8359916-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001042681.2(RERE):​c.3466G>T​(p.Gly1156Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1156R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24
• Publications: 2 publications found

Genes affected

RERE (HGNC:9965): (arginine-glutamic acid dipeptide repeats) This gene encodes a member of the atrophin family of arginine-glutamic acid (RE) dipeptide repeat-containing proteins. The encoded protein co-localizes with a transcription factor in the nucleus, and its overexpression triggers apoptosis. A similar protein in mouse associates with histone deacetylase and is thought to function as a transcriptional co-repressor during embryonic development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RERE Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without anomalies of the brain, eye, or heart

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	NM_001042681.2	MANE Select	c.3466G>T	p.Gly1156Trp	missense	Exon 19 of 23	NP_001036146.1	Q9P2R6-1
	RERE	NM_012102.4		c.3466G>T	p.Gly1156Trp	missense	Exon 20 of 24	NP_036234.3
	RERE	NM_001042682.2		c.1804G>T	p.Gly602Trp	missense	Exon 9 of 13	NP_001036147.1	Q9P2R6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	ENST00000400908.7	TSL:1 MANE Select	c.3466G>T	p.Gly1156Trp	missense	Exon 19 of 23	ENSP00000383700.2	Q9P2R6-1
	RERE	ENST00000337907.7	TSL:1	c.3466G>T	p.Gly1156Trp	missense	Exon 20 of 24	ENSP00000338629.3	Q9P2R6-1
	RERE	ENST00000476556.5	TSL:1	c.1804G>T	p.Gly602Trp	missense	Exon 9 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.50		Gain of catalytic residue at L1154 (P = 0.0101)
MVP		0.64
MPC		0.42
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.17
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs766951273; hg19: chr1-8419976;