rs878853270

Positions:

• chr1-8358750-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.97

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 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 id is 236217.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-8358750-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RERE	NM_001042681.2	c.3785C>G	p.Pro1262Arg	missense_variant	20/23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.3785C>G	p.Pro1262Arg	missense_variant	21/24		NP_036234.3
RERE	NM_001042682.2	c.2123C>G	p.Pro708Arg	missense_variant	10/13		NP_001036147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7	c.3785C>G	p.Pro1262Arg	missense_variant	20/23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2016

The P1262R variant in the RERE gene has been reported previously in an individual with microcephaly, facial dysmorphism, and multiple congenital anomalies (Fregeau et al., 2016); this variant has not been reported otherwise in the literature, to our knowledge. The P1262R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1262R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P1262R as a likely pathogenic variant. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.8	M;.;.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.94
MutPred		0.52		Gain of solvent accessibility (P = 0.0055);.;.;Gain of solvent accessibility (P = 0.0055);
MVP		0.94
MPC		0.38
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.87

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: rs878853270; hg19: chr1-8418810;