Genetic Variant RERE:p.Lys1190_Glu1191del (chr1-8359808-GCTCCTT-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3BP3BP6_Very_StrongBS1BS2

The NM_001042681.2(RERE):c.3568_3573delAAGGAG(p.Lys1190_Glu1191del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,604,552 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K1190K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 30)

Exomes 𝑓: 0.0038 ( 21 hom. )

Consequence

RERE
NM_001042681.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.83

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 -16 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP3

Nonframeshift variant in repetitive region in NM_001042681.2

BP6

Variant 1-8359808-GCTCCTT-G is Benign according to our data. Variant chr1-8359808-GCTCCTT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 715993.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 = 0.0041 (623/151768) while in subpopulation AFR AF = 0.00647 (268/41406). AF 95% confidence interval is 0.00584. There are 2 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 623 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_3573delAAGGAG	p.Lys1190_Glu1191del	conservative_inframe_deletion	Exon 19 of 23	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4		c.3568_3573delAAGGAG	p.Lys1190_Glu1191del	conservative_inframe_deletion	Exon 20 of 24	NP_036234.3
RERE	NM_001042682.2		c.1906_1911delAAGGAG	p.Lys636_Glu637del	conservative_inframe_deletion	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_3573delAAGGAG	p.Lys1190_Glu1191del	conservative_inframe_deletion	Exon 19 of 23	ENSP00000383700.2	Q9P2R6-1
RERE	ENST00000337907.7	TSL:1	c.3568_3573delAAGGAG	p.Lys1190_Glu1191del	conservative_inframe_deletion	Exon 20 of 24	ENSP00000338629.3	Q9P2R6-1
RERE	ENST00000476556.5	TSL:1	c.1906_1911delAAGGAG	p.Lys636_Glu637del	conservative_inframe_deletion	Exon 9 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

621

AN:

151650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00401

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00581

Gnomad SAS

AF:

0.00251

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00342

Gnomad OTH

AF:

0.00672

GnomAD2 exomes

AF:

0.00386

AC:

938

AN:

243122

AF XY:

0.00365

show subpopulations

Gnomad AFR exome

AF:

0.00830

Gnomad AMR exome

AF:

0.00537

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.00586

Gnomad FIN exome

AF:

0.000734

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00384

AC:

5585

AN:

1452784

Hom.:

AF XY:

0.00381

AC XY:

2752

AN XY:

723162

show subpopulations

African (AFR)

AF:

0.00682

AC:

228

AN:

33448

American (AMR)

AF:

0.00510

AC:

228

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

26126

East Asian (EAS)

AF:

0.00769

AC:

305

AN:

39680

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86194

European-Finnish (FIN)

AF:

0.000968

AC:

AN:

45434

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00387

AC:

4298

AN:

1111194

Other (OTH)

AF:

0.00332

AC:

200

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

353

706

1058

1411

1764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00410

AC:

623

AN:

151768

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

276

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.00647

AC:

268

AN:

41406

American (AMR)

AF:

0.00394

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00582

AC:

AN:

5152

South Asian (SAS)

AF:

0.00251

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00343

AC:

233

AN:

67860

Other (OTH)

AF:

0.00665

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

125

156

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:

0.00151

Hom.:

Bravo

AF:

0.00450

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

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

RERE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.8

Mutation Taster

=168/32

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over