1-8355558-G-T

Position:

chr1-8355558-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042681.2(RERE):c.4528C>A(p.Pro1510Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,604,514 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1510L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 2 hom. )

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.07

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009254128).

BP6

Variant 1-8355558-G-T is Benign according to our data. Variant chr1-8355558-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 783922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00504 (768/152324) while in subpopulation AFR AF= 0.0152 (631/41578). AF 95% confidence interval is 0.0142. There are 4 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 768 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RERE	NM_001042681.2 linkuse as main transcript	c.4528C>A	p.Pro1510Thr	missense_variant	22/23	ENST00000400908.7	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4 linkuse as main transcript	c.4528C>A	p.Pro1510Thr	missense_variant	23/24		NP_036234.3	Q9P2R6-1
RERE	NM_001042682.2 linkuse as main transcript	c.2866C>A	p.Pro956Thr	missense_variant	12/13		NP_001036147.1	Q9P2R6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7 linkuse as main transcript	c.4528C>A	p.Pro1510Thr	missense_variant	22/23	1	NM_001042681.2	ENSP00000383700.2		Q9P2R6-1

Frequencies

GnomAD3 genomes

AF:

0.00505

AC:

768

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00164

AC:

383

AN:

234062

Hom.:

AF XY:

0.00127

AC XY:

163

AN XY:

128358

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.000854

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.000826

AC:

1199

AN:

1452190

Hom.:

Cov.:

AF XY:

0.000770

AC XY:

555

AN XY:

721154

show subpopulations

Gnomad4 AFR exome

AF:

0.0129

Gnomad4 AMR exome

AF:

0.00307

Gnomad4 ASJ exome

AF:

0.000698

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000440

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00504

AC:

768

AN:

152324

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

362

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.00529

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000618

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.000793

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00173

AC:

209

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RERE-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;.;.;.;D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D;D;D;D

MetaRNN

Benign

0.0093

T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.9

L;.;.;.;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

D;D;N;D;D;D

REVEL

Benign

0.21

Sift

Benign

0.033

D;T;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;.

Polyphen

0.21

B;.;.;.;B;.

Vest4

0.35

MVP

0.39

MPC

0.40

ClinPred

0.063

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over