1-8355495-C-A

Variant names:

• chr1-8355495-C-A
• rs762564525
• NM_001042681.2:c.4591G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001042681.2(RERE):​c.4591G>T​(p.Ala1531Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,452 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: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.90

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_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2	c.4591G>T	p.Ala1531Ser	missense_variant	Exon 22 of 23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.4591G>T	p.Ala1531Ser	missense_variant	Exon 23 of 24		NP_036234.3
RERE	NM_001042682.2	c.2929G>T	p.Ala977Ser	missense_variant	Exon 12 of 13		NP_001036147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7	c.4591G>T	p.Ala1531Ser	missense_variant	Exon 22 of 23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 243130 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460452 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 726528

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: 0.0000189

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

RERE-related disorder Uncertain:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RERE c.4591G>T variant is predicted to result in the amino acid substitution p.Ala1531Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4591G>T (p.A1531S) alteration is located in exon 23 (coding exon 21) of the RERE gene. This alteration results from a G to T substitution at nucleotide position 4591, causing the alanine (A) at amino acid position 1531 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M;.;.;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;T;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.77
MutPred		0.63		Gain of relative solvent accessibility (P = 0.09);.;.;.;Gain of relative solvent accessibility (P = 0.09);
MVP		0.85
MPC		0.33
ClinPred		0.70	D
GERP RS		6.0
Varity_R		0.36
gMVP		0.55

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: rs762564525; hg19: chr1-8415555;