1-8359808-G-GCTCCTTCTCCTT

Variant names:

• chr1-8359808-G-GCTCCTTCTCCTT
• rs147985313
• NM_001042681.2:c.3562_3573dupAAGGAGAAGGAG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001042681.2(RERE):​c.3562_3573dupAAGGAGAAGGAG​(p.Glu1191_Arg1192insLysGluLysGlu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,452,804 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RERE NM_001042681.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001042681.2
• BS2: High AC in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	NM_001042681.2	MANE Select	c.3562_3573dupAAGGAGAAGGAG	p.Glu1191_Arg1192insLysGluLysGlu	conservative_inframe_insertion	Exon 19 of 23	NP_001036146.1	Q9P2R6-1
	RERE	NM_012102.4		c.3562_3573dupAAGGAGAAGGAG	p.Glu1191_Arg1192insLysGluLysGlu	conservative_inframe_insertion	Exon 20 of 24	NP_036234.3
	RERE	NM_001042682.2		c.1900_1911dupAAGGAGAAGGAG	p.Glu637_Arg638insLysGluLysGlu	conservative_inframe_insertion	Exon 9 of 13	NP_001036147.1	Q9P2R6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	ENST00000400908.7	TSL:1 MANE Select	c.3562_3573dupAAGGAGAAGGAG	p.Glu1191_Arg1192insLysGluLysGlu	conservative_inframe_insertion	Exon 19 of 23	ENSP00000383700.2	Q9P2R6-1
	RERE	ENST00000337907.7	TSL:1	c.3562_3573dupAAGGAGAAGGAG	p.Glu1191_Arg1192insLysGluLysGlu	conservative_inframe_insertion	Exon 20 of 24	ENSP00000338629.3	Q9P2R6-1
	RERE	ENST00000476556.5	TSL:1	c.1900_1911dupAAGGAGAAGGAG	p.Glu637_Arg638insLysGluLysGlu	conservative_inframe_insertion	Exon 9 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000165 AC: 4 AN: 243122 AF XY: 0.0000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1452804 Hom.: 0 Cov.: 33 AF XY: 0.00000968 AC XY: 7 AN XY: 723170

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111198

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=48/52	disease causing

Splicing

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

Other links and lift over

dbSNP: rs147985313; hg19: chr1-8419868;