Genetic Variant RERE:p.Pro1022Thr (chr1-8360443-G-T) – ACMG Classification: Benign (-14 pts)

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	NM_001042681.2	MANE Select	c.3064C>A	p.Pro1022Thr	missense	Exon 18 of 23	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4		c.3064C>A	p.Pro1022Thr	missense	Exon 19 of 24	NP_036234.3
RERE	NM_001042682.2		c.1402C>A	p.Pro468Thr	missense	Exon 8 of 13	NP_001036147.1	Q9P2R6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	ENST00000400908.7	TSL:1 MANE Select	c.3064C>A	p.Pro1022Thr	missense	Exon 18 of 23	ENSP00000383700.2	Q9P2R6-1
RERE	ENST00000337907.7	TSL:1	c.3064C>A	p.Pro1022Thr	missense	Exon 19 of 24	ENSP00000338629.3	Q9P2R6-1
RERE	ENST00000476556.5	TSL:1	c.1402C>A	p.Pro468Thr	missense	Exon 8 of 13	ENSP00000422246.1	Q9P2R6-2

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.75

M_CAP

Benign

0.046

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

REVEL

Benign

0.096

Sift

Benign

0.26

Sift4G

Uncertain

0.015

Polyphen

0.0

Vest4

0.19

MutPred

0.37

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over