chr1-8358216-TGGTGGAGGTGGA-T

Variant names:

• chr1-8358216-TGGTGGAGGTGGA-T
• rs1064793252
• NM_001042681.2:c.4307_4318delTCCACCTCCACC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM1 PP3 PP5_Very_Strong BP3

The NM_001042681.2(RERE):​c.4307_4318delTCCACCTCCACC​(p.Leu1436_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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RERE NM_001042681.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.97
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001042681.2
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-8358216-TGGTGGAGGTGGA-T is Pathogenic according to our data. Variant chr1-8358216-TGGTGGAGGTGGA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2442107.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	NM_001042681.2	MANE Select	c.4307_4318delTCCACCTCCACC	p.Leu1436_His1439del	disruptive_inframe_deletion	Exon 20 of 23	NP_001036146.1
	RERE	NM_012102.4		c.4307_4318delTCCACCTCCACC	p.Leu1436_His1439del	disruptive_inframe_deletion	Exon 21 of 24	NP_036234.3
	RERE	NM_001042682.2		c.2645_2656delTCCACCTCCACC	p.Leu882_His885del	disruptive_inframe_deletion	Exon 10 of 13	NP_001036147.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	ENST00000400908.7	TSL:1 MANE Select	c.4307_4318delTCCACCTCCACC	p.Leu1436_His1439del	disruptive_inframe_deletion	Exon 20 of 23	ENSP00000383700.2
	RERE	ENST00000337907.7	TSL:1	c.4307_4318delTCCACCTCCACC	p.Leu1436_His1439del	disruptive_inframe_deletion	Exon 21 of 24	ENSP00000338629.3
	RERE	ENST00000476556.5	TSL:1	c.2645_2656delTCCACCTCCACC	p.Leu882_His885del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000422246.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs1064793252; hg19: chr1-8418276;