chr1-8359808-G-GCTCCTT

Variant names:

• chr1-8359808-G-GCTCCTT
• rs147985313
• NM_001042681.2:c.3568_3573dupAAGGAG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001042681.2(RERE):​c.3568_3573dupAAGGAG​(p.Glu1191_Arg1192insLysGlu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,604,560 control chromosomes in the GnomAD database, including 77 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (42 hom.)
• Consequence: RERE NM_001042681.2 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001042681.2
• BP6: Variant 1-8359808-G-GCTCCTT is Benign according to our data. Variant chr1-8359808-G-GCTCCTT is described in ClinVar as Benign. ClinVar VariationId is 777879.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 = 0.0128 (1949/151758) while in subpopulation AFR AF = 0.0428 (1772/41398). AF 95% confidence interval is 0.0411. There are 35 homozygotes in GnomAd4. There are 939 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1949 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.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 19 of 23	NP_001036146.1	Q9P2R6-1
	RERE	NM_012102.4		c.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 20 of 24	NP_036234.3
	RERE	NM_001042682.2		c.1906_1911dupAAGGAG	p.Glu637_Arg638insLysGlu	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.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 19 of 23	ENSP00000383700.2	Q9P2R6-1
	RERE	ENST00000337907.7	TSL:1	c.3568_3573dupAAGGAG	p.Glu1191_Arg1192insLysGlu	conservative_inframe_insertion	Exon 20 of 24	ENSP00000338629.3	Q9P2R6-1
	RERE	ENST00000476556.5	TSL:1	c.1906_1911dupAAGGAG	p.Glu637_Arg638insLysGlu	conservative_inframe_insertion	Exon 9 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1947 AN: 151640 Hom.: 35 Cov.: 30

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00697

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00396 AC: 962 AN: 243122 AF XY: 0.00308

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.000493

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00162 AC: 2355 AN: 1452802 Hom.: 42 Cov.: 33 AF XY: 0.00144 AC XY: 1043 AN XY: 723170

African (AFR) AF: 0.0439 AC: 1467 AN: 33446

American (AMR) AF: 0.00416 AC: 186 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26126

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39680

South Asian (SAS) AF: 0.000476 AC: 41 AN: 86194

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45450

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5752

European-Non Finnish (NFE) AF: 0.000347 AC: 386 AN: 1111198

Other (OTH) AF: 0.00360 AC: 217 AN: 60292

GnomAD4 genome AF: 0.0128 AC: 1949 AN: 151758 Hom.: 35 Cov.: 30 AF XY: 0.0127 AC XY: 939 AN XY: 74164

African (AFR) AF: 0.0428 AC: 1772 AN: 41398

American (AMR) AF: 0.00696 AC: 106 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5152

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67858

Other (OTH) AF: 0.0109 AC: 23 AN: 2106

Alfa AF: 0.000700 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (1)
-	-	1	not provided (1)
-	-	1	See cases (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; COSMIC: COSV61946393; COSMIC: COSV61946393;