1-8360443-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042681.2(RERE):c.3064C>G(p.Pro1022Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1022S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0055 ( 8 hom., cov: 17)

Exomes 𝑓: 0.00063 ( 12 hom. )

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.67

Publications

1 publications found

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 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

RERE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027897656).

BP6

Variant 1-8360443-G-C is Benign according to our data. Variant chr1-8360443-G-C is described in ClinVar as Benign. ClinVar VariationId is 445630.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 = 0.00553 (774/139868) while in subpopulation AFR AF = 0.0202 (751/37116). AF 95% confidence interval is 0.019. There are 8 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.

BS2

High AC in GnomAd4 at 774 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2 link	c.3064C>G	p.Pro1022Ala	missense_variant	Exon 18 of 23	ENST00000400908.7	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4 link	c.3064C>G	p.Pro1022Ala	missense_variant	Exon 19 of 24		NP_036234.3	Q9P2R6-1
RERE	NM_001042682.2 link	c.1402C>G	p.Pro468Ala	missense_variant	Exon 8 of 13		NP_001036147.1	Q9P2R6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7 link	c.3064C>G	p.Pro1022Ala	missense_variant	Exon 18 of 23	1	NM_001042681.2	ENSP00000383700.2		Q9P2R6-1

Frequencies

GnomAD3 genomes

AF:

0.00555

AC:

776

AN:

139774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000745

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000156

Gnomad OTH

AF:

0.00261

GnomAD2 exomes

AF:

0.00148

AC:

AN:

38408

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.0150

Gnomad AMR exome

AF:

0.000282

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:

0.000632

AC:

519

AN:

821502

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

230

AN XY:

408144

show subpopulations

African (AFR)

AF:

0.0229

AC:

417

AN:

18202

American (AMR)

AF:

0.000625

AC:

AN:

14404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15150

East Asian (EAS)

AF:

0.00

AC:

AN:

29218

South Asian (SAS)

AF:

0.000327

AC:

AN:

48940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29840

Middle Eastern (MID)

AF:

0.000379

AC:

AN:

2642

European-Non Finnish (NFE)

AF:

0.0000272

AC:

AN:

625714

Other (OTH)

AF:

0.00158

AC:

AN:

37392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.626

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00553

AC:

774

AN:

139868

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

342

AN XY:

67778

show subpopulations

African (AFR)

AF:

0.0202

AC:

751

AN:

37116

American (AMR)

AF:

0.000984

AC:

AN:

14226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3326

East Asian (EAS)

AF:

0.00

AC:

AN:

4564

South Asian (SAS)

AF:

0.000746

AC:

AN:

4024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000156

AC:

AN:

63976

Other (OTH)

AF:

0.00259

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.573

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.00776

ESP6500AA

AF:

0.00725

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000948

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

RERE-related disorder

Benign:1

Mar 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.13

T;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.67

.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;.;M

PhyloP100

1.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.085

Sift

Benign

0.068

T;T;T;T

Sift4G

Uncertain

0.026

D;T;D;D

Polyphen

0.0020

B;B;.;B

Vest4

0.24

MVP

0.56

MPC

0.34

ClinPred

0.022

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.028

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over