1-8355536-A-T

Position:

• chr1-8355536-A-T

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.4550T>A​(p.Leu1517Gln) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.52

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, 0.87
• PP5: Variant 1-8355536-A-T is Pathogenic according to our data. Variant chr1-8355536-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452752.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RERE	NM_001042681.2	c.4550T>A	p.Leu1517Gln	missense_variant	22/23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.4550T>A	p.Leu1517Gln	missense_variant	23/24		NP_036234.3
RERE	NM_001042682.2	c.2888T>A	p.Leu963Gln	missense_variant	12/13		NP_001036147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7	c.4550T>A	p.Leu1517Gln	missense_variant	22/23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2017

The L1517Q variant in the RERE gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016). The 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L1517Q as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.;.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.8	M;.;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;D;N;D;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;D;.
Vest4		0.84
MutPred		0.72		Loss of helix (P = 0.0626);.;.;.;Loss of helix (P = 0.0626);.;
MVP		0.85
MPC		0.37
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.76
gMVP		0.80

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: rs1553153669; hg19: chr1-8415596;