1-8360443-G-A

Variant names:

• chr1-8360443-G-A
• rs202121539
• NM_001042681.2:c.3064C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001042681.2(RERE):​c.3064C>T​(p.Pro1022Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1022A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.67
• Publications: 1 publications found

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]

RERE Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without anomalies of the brain, eye, or heart

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07562131).
• BP6: Variant 1-8360443-G-A is Benign according to our data. Variant chr1-8360443-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3025882.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2	c.3064C>T	p.Pro1022Ser	missense_variant	Exon 18 of 23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.3064C>T	p.Pro1022Ser	missense_variant	Exon 19 of 24		NP_036234.3
RERE	NM_001042682.2	c.1402C>T	p.Pro468Ser	missense_variant	Exon 8 of 13		NP_001036147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7	c.3064C>T	p.Pro1022Ser	missense_variant	Exon 18 of 23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.0000521 AC: 2 AN: 38408 AF XY: 0.0000500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000141

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000699

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000730 AC: 6 AN: 821502 Hom.: 0 Cov.: 12 AF XY: 0.00000980 AC XY: 4 AN XY: 408144

African (AFR) AF: 0.00 AC: 0 AN: 18202

American (AMR) AF: 0.000139 AC: 2 AN: 14404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15150

East Asian (EAS) AF: 0.00 AC: 0 AN: 29218

South Asian (SAS) AF: 0.00 AC: 0 AN: 48940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2642

European-Non Finnish (NFE) AF: 0.00000639 AC: 4 AN: 625714

Other (OTH) AF: 0.00 AC: 0 AN: 37392

GnomAD4 genome Cov.: 17

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3064C>T (p.P1022S) alteration is located in exon 19 (coding exon 17) of the RERE gene. This alteration results from a C to T substitution at nucleotide position 3064, causing the proline (P) at amino acid position 1022 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RERE: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.41
DEOGEN2	Benign	0.085	T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.076	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;L
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.77	N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.066	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.23
MutPred		0.33		Loss of catalytic residue at P1021 (P = 0.0191);.;.;Loss of catalytic residue at P1021 (P = 0.0191);
MVP		0.42
MPC		0.36
ClinPred		0.058	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.023
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs202121539; hg19: chr1-8420503;