Genetic Variant RERE:p.Leu1438_His1439del (chr1-8358216-TGGTGGA-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM2PP3PP5_Very_StrongBP3

The NM_001042681.2(RERE):c.4313_4318delTCCACC(p.Leu1438_His1439del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1438L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RERE
NM_001042681.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.97

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001042681.2

PM2

Very rare variant in population databases, with high coverage;

PP3

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

PP5

Variant 1-8358216-TGGTGGA-T is Pathogenic according to our data. Variant chr1-8358216-TGGTGGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2580782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP3

Nonframeshift variant in repetitive region in NM_001042681.2

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
RERE	NM_001042681.2	MANE Select	c.4313_4318delTCCACC	p.Leu1438_His1439del	disruptive_inframe_deletion	Exon 20 of 23	NP_001036146.1
RERE	NM_012102.4		c.4313_4318delTCCACC	p.Leu1438_His1439del	disruptive_inframe_deletion	Exon 21 of 24	NP_036234.3
RERE	NM_001042682.2		c.2651_2656delTCCACC	p.Leu884_His885del	disruptive_inframe_deletion	Exon 10 of 13	NP_001036147.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RERE	ENST00000400908.7	TSL:1 MANE Select	c.4313_4318delTCCACC	p.Leu1438_His1439del	disruptive_inframe_deletion	Exon 20 of 23	ENSP00000383700.2
RERE	ENST00000337907.7	TSL:1	c.4313_4318delTCCACC	p.Leu1438_His1439del	disruptive_inframe_deletion	Exon 21 of 24	ENSP00000338629.3
RERE	ENST00000476556.5	TSL:1	c.2651_2656delTCCACC	p.Leu884_His885del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000422246.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443026

Hom.:

AF XY:

0.00

AC XY:

AN XY:

713460

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25786

East Asian (EAS)

AF:

0.00

AC:

AN:

39166

South Asian (SAS)

AF:

0.00

AC:

AN:

85508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096774

Other (OTH)

AF:

0.00

AC:

AN:

59462

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

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 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

Mutation Taster

=51/149

disease causing

(source)

Splicing

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

Publications

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1-8358216-TGGTGGAGGTGGA-TGGTGGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over