Genetic Variant RERE:p.Glu1191_Arg1192insLysGlu (chr1-8359808-G-GCTCCTT) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001042681.2(RERE):c.3568_3573dupAAGGAG(p.Glu1191_Arg1192insLysGlu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,604,560 control chromosomes in the GnomAD database, including 77 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 30)

Exomes 𝑓: 0.0016 ( 42 hom. )

Consequence

RERE
NM_001042681.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.32

Publications

2 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001042681.2

BP6

Variant 1-8359808-G-GCTCCTT is Benign according to our data. Variant chr1-8359808-G-GCTCCTT is described in ClinVar as Benign. ClinVar VariationId is 777879.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 = 0.0128 (1949/151758) while in subpopulation AFR AF = 0.0428 (1772/41398). AF 95% confidence interval is 0.0411. There are 35 homozygotes in GnomAd4. There are 939 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 1949 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.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 19 of 23	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4		c.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 20 of 24	NP_036234.3
RERE	NM_001042682.2		c.1906_1911dupAAGGAG	p.Glu637_Arg638insLysGlu	conservative_inframe_insertion	Exon 9 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.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 19 of 23	ENSP00000383700.2	Q9P2R6-1
RERE	ENST00000337907.7	TSL:1	c.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 20 of 24	ENSP00000338629.3	Q9P2R6-1
RERE	ENST00000476556.5	TSL:1	c.1906_1911dupAAGGAG	p.Glu637_Arg638insLysGlu	conservative_inframe_insertion	Exon 9 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1947

AN:

151640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00697

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.00126

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000486

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00396

AC:

962

AN:

243122

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.00398

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.000493

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000448

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00162

AC:

2355

AN:

1452802

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1043

AN XY:

723170

show subpopulations

African (AFR)

AF:

0.0439

AC:

1467

AN:

33446

American (AMR)

AF:

0.00416

AC:

186

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.000880

AC:

AN:

26126

East Asian (EAS)

AF:

0.000353

AC:

AN:

39680

South Asian (SAS)

AF:

0.000476

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.0000220

AC:

AN:

45450

Middle Eastern (MID)

AF:

0.00348

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000347

AC:

386

AN:

1111198

Other (OTH)

AF:

0.00360

AC:

217

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0128

AC:

1949

AN:

151758

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

939

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.0428

AC:

1772

AN:

41398

American (AMR)

AF:

0.00696

AC:

106

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000582

AC:

AN:

5152

South Asian (SAS)

AF:

0.00126

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

67858

Other (OTH)

AF:

0.0109

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000700

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (1)

not provided (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=48/52

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-8359808-GCTCCTTCTCCTT-GCTCCTTCTCCTTCTCCTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over