Genetic Variant RERE:p.Gly1083Glu (chr1-8360259-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042681.2(RERE):c.3248G>A(p.Gly1083Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,574,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1083V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08426753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RERE	NM_001042681.2 link	c.3248G>A	p.Gly1083Glu	missense_variant	Exon 18 of 23	ENST00000400908.7	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4 link	c.3248G>A	p.Gly1083Glu	missense_variant	Exon 19 of 24		NP_036234.3	Q9P2R6-1
RERE	NM_001042682.2 link	c.1586G>A	p.Gly529Glu	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.3248G>A	p.Gly1083Glu	missense_variant	Exon 18 of 23	1	NM_001042681.2	ENSP00000383700.2		Q9P2R6-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32740

American (AMR)

AF:

0.00

AC:

AN:

40294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

37820

South Asian (SAS)

AF:

0.00

AC:

AN:

81514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093354

Other (OTH)

AF:

0.00

AC:

AN:

58850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000661

AC:

AN:

151336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41124

American (AMR)

AF:

0.00

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67830

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.098

T;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.86

.;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.084

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.;L

PhyloP100

0.69

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.85

N;N;N;N

REVEL

Benign

0.041

Sift

Uncertain

0.026

D;D;D;D

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.049

B;B;.;B

Vest4

0.20

MutPred

0.44

Loss of catalytic residue at S1085 (P = 0.0427);.;.;Loss of catalytic residue at S1085 (P = 0.0427);

MVP

0.33

MPC

0.46

ClinPred

0.12

GERP RS

0.89

Varity_R

0.064

gMVP

0.21

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Computational scores

Splicing

Publications

Other links and lift over