chr1-8360443-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001042681.2(RERE):c.3064C>A(p.Pro1022Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. P1022S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000056 ( 1 hom. )

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037635326).

BP6

Variant 1-8360443-G-T is Benign according to our data. Variant chr1-8360443-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3432119.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000056 (46/821502) while in subpopulation EAS AF = 0.000171 (5/29218). AF 95% confidence interval is 0.0000674. There are 1 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2 link	c.3064C>A	p.Pro1022Thr	missense_variant	Exon 18 of 23	ENST00000400908.7	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4 link	c.3064C>A	p.Pro1022Thr	missense_variant	Exon 19 of 24		NP_036234.3	Q9P2R6-1
RERE	NM_001042682.2 link	c.1402C>A	p.Pro468Thr	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>A	p.Pro1022Thr	missense_variant	Exon 18 of 23	1	NM_001042681.2	ENSP00000383700.2		Q9P2R6-1

Frequencies

GnomAD3 genomes

AF:

0.0000429

AC:

AN:

139780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000540

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000704

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000218

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000313

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000781

AC:

AN:

38408

AF XY:

0.000150

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000560

AC:

AN:

821502

Hom.:

Cov.:

AF XY:

0.0000637

AC XY:

AN XY:

408144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18202

American (AMR)

AF:

0.00

AC:

AN:

14404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15150

East Asian (EAS)

AF:

0.000171

AC:

AN:

29218

South Asian (SAS)

AF:

0.000102

AC:

AN:

48940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2642

European-Non Finnish (NFE)

AF:

0.0000543

AC:

AN:

625714

Other (OTH)

AF:

0.0000535

AC:

AN:

37392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.624

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000429

AC:

AN:

139874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67780

show subpopulations

African (AFR)

AF:

0.0000539

AC:

AN:

37122

American (AMR)

AF:

0.0000703

AC:

AN:

14226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3326

East Asian (EAS)

AF:

0.000219

AC:

AN:

4564

South Asian (SAS)

AF:

0.00

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:

0.0000313

AC:

AN:

63976

Other (OTH)

AF:

0.00

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000211

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Dec 10, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.16

T;.;.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.75

.;T;T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.038

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;.;L

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.096

Sift

Benign

0.26

T;T;T;T

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.0

B;B;.;B

Vest4

0.19

MutPred

0.37

Loss of catalytic residue at P1021 (P = 0.0191);.;.;Loss of catalytic residue at P1021 (P = 0.0191);

MVP

0.45

MPC

0.40

ClinPred

0.074

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.044

gMVP

0.28

Mutation Taster

=97/3

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over