rs878853011

chr1-8360361-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.79

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]

ACMG classification

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/exons	MANE	UniProt
RERE	NM_001042681.2	c.3146C>T	p.Pro1049Leu	missense_variant	18/23	ENST00000400908.7
RERE	NM_012102.4	c.3146C>T	p.Pro1049Leu	missense_variant	19/24
RERE	NM_001042682.2	c.1484C>T	p.Pro495Leu	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RERE	ENST00000400908.7	c.3146C>T	p.Pro1049Leu	missense_variant	18/23	1	NM_001042681.2	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 148854 Hom.: 0 Cov.: 24 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.: 35

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 148854 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 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

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 25, 2016

- -

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Daryl Scott Lab, Baylor College of Medicine

Sep 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.;D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
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	D
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

Other links and lift over

dbSNP: rs878853011; hg19: chr1-8420421;