dbSNP rs878853011: RERE:p.Pro1049Leu (chr1-8360361-G-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001042681.2(RERE):c.3146C>T(p.Pro1049Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 24)

Failed GnomAD Quality Control

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-8360361-G-A is Pathogenic according to our data. Variant chr1-8360361-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-8360361-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.28343782). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2 link	c.3146C>T	p.Pro1049Leu	missense_variant	Exon 18 of 23	ENST00000400908.7	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4 link	c.3146C>T	p.Pro1049Leu	missense_variant	Exon 19 of 24		NP_036234.3	Q9P2R6-1
RERE	NM_001042682.2 link	c.1484C>T	p.Pro495Leu	missense_variant	Exon 8 of 13		NP_001036147.1	Q9P2R6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7 link	c.3146C>T	p.Pro1049Leu	missense_variant	Exon 18 of 23	1	NM_001042681.2	ENSP00000383700.2		Q9P2R6-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148854

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

148854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72558

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Apr 25, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Sep 12, 2017

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.0060

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;.;.;D

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

M;.;.;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.0

B;B;.;B

Vest4

0.48

MutPred

0.50

Loss of glycosylation at P1049 (P = 0.0273);.;.;Loss of glycosylation at P1049 (P = 0.0273);

MVP

0.55

MPC

0.36

ClinPred

0.96

GERP RS

4.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.28

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over