1-8359916-C-T

Position:

• chr1-8359916-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001042681.2(RERE):​c.3466G>A​(p.Gly1156Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1156W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.24

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RERE	NM_001042681.2	c.3466G>A	p.Gly1156Arg	missense_variant	19/23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.3466G>A	p.Gly1156Arg	missense_variant	20/24		NP_036234.3
RERE	NM_001042682.2	c.1804G>A	p.Gly602Arg	missense_variant	9/13		NP_001036147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RERE	ENST00000400908.7	c.3466G>A	p.Gly1156Arg	missense_variant	19/23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250798 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461054 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 726870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 30 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.3466G>A(p.Gly1156Arg) variant in RERE gene has been previously reported as a de novo in a patient within a group of patients with RERErelated disorder (Fregeau B et al,2016). The variant has been submitted to ClinVar as a Pathogenic variant based on the same study. The p.Gly1156Arg variant is observed in 0.002% alleles from individuals in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Gly at position 1156 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gly1156Arg in RERE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Though the variant has been reported previously , it has been classified as Uncertain Significance due to it's presence in the gnomAD database. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M;.;.;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.025	D;T;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.52
MutPred		0.53		Gain of solvent accessibility (P = 0.0171);.;.;Gain of solvent accessibility (P = 0.0171);
MVP		0.56
MPC		0.42
ClinPred		0.70	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs766951273; hg19: chr1-8419976;