chr1-8358216-T-TGGTGGA

Variant names:

• chr1-8358216-T-TGGTGGA
• rs1064793252
• NM_001042681.2:c.4313_4318dupTCCACC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM2 PP3 PP5_Very_Strong BP3

The NM_001042681.2(RERE):​c.4313_4318dupTCCACC​(p.Leu1438_His1439dup) variant causes a conservative inframe insertion 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RERE NM_001042681.2 conservative_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.97
• Publications: 3 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 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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-T-TGGTGGA is Pathogenic according to our data. Variant chr1-8358216-T-TGGTGGA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 418456.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.4313_4318dupTCCACC	p.Leu1438_His1439dup	conservative_inframe_insertion	Exon 20 of 23	NP_001036146.1
	RERE	NM_012102.4		c.4313_4318dupTCCACC	p.Leu1438_His1439dup	conservative_inframe_insertion	Exon 21 of 24	NP_036234.3
	RERE	NM_001042682.2		c.2651_2656dupTCCACC	p.Leu884_His885dup	conservative_inframe_insertion	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.4313_4318dupTCCACC	p.Leu1438_His1439dup	conservative_inframe_insertion	Exon 20 of 23	ENSP00000383700.2
	RERE	ENST00000337907.7	TSL:1	c.4313_4318dupTCCACC	p.Leu1438_His1439dup	conservative_inframe_insertion	Exon 21 of 24	ENSP00000338629.3
	RERE	ENST00000476556.5	TSL:1	c.2651_2656dupTCCACC	p.Leu884_His885dup	conservative_inframe_insertion	Exon 10 of 13	ENSP00000422246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (5)
1	-	-	CHARGE syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=27/73	disease causing (ClinVar)

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;