dbSNP rs878853270: RERE:p.Pro1262Arg (chr1-8358750-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_001042681.2(RERE):c.3785C>G(p.Pro1262Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1262T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.97

Publications

1 publications found

Variant links:

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

RERE links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

PP5

Variant 1-8358750-G-C is Pathogenic according to our data. Variant chr1-8358750-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 236217.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	NM_001042681.2	MANE Select	c.3785C>G	p.Pro1262Arg	missense	Exon 20 of 23	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4		c.3785C>G	p.Pro1262Arg	missense	Exon 21 of 24	NP_036234.3
RERE	NM_001042682.2		c.2123C>G	p.Pro708Arg	missense	Exon 10 of 13	NP_001036147.1	Q9P2R6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	ENST00000400908.7	TSL:1 MANE Select	c.3785C>G	p.Pro1262Arg	missense	Exon 20 of 23	ENSP00000383700.2	Q9P2R6-1
RERE	ENST00000337907.7	TSL:1	c.3785C>G	p.Pro1262Arg	missense	Exon 21 of 24	ENSP00000338629.3	Q9P2R6-1
RERE	ENST00000476556.5	TSL:1	c.2123C>G	p.Pro708Arg	missense	Exon 10 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.8

PhyloP100

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.52

Gain of solvent accessibility (P = 0.0055)

MVP

0.94

MPC

0.38

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.87

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over