1-8355515-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042681.2(RERE):c.4571C>T(p.Ser1524Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RERE	NM_001042681.2	c.4571C>T	p.Ser1524Leu	missense_variant	22/23	ENST00000400908.7
RERE	NM_012102.4	c.4571C>T	p.Ser1524Leu	missense_variant	23/24
RERE	NM_001042682.2	c.2909C>T	p.Ser970Leu	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RERE	ENST00000400908.7	c.4571C>T	p.Ser1524Leu	missense_variant	22/23	1	NM_001042681.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459556 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.4571C>T (p.S1524L) alteration is located in exon 23 (coding exon 21) of the RERE gene. This alteration results from a C to T substitution at nucleotide position 4571, causing the serine (S) at amino acid position 1524 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 30, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.8	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.9	D;D;N;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;T;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.79
MutPred		0.65		Gain of stability (P = 0.0432);.;.;.;Gain of stability (P = 0.0432);
MVP		0.84
MPC		0.32
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.49
gMVP		0.72

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: rs1641253525; hg19: chr1-8415575;