chr1-8359916-C-A

Position:

• chr1-8359916-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001042681.2(RERE):​c.3466G>T​(p.Gly1156Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G1156R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-8359916-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RERE	NM_001042681.2	c.3466G>T	p.Gly1156Trp	missense_variant	19/23	ENST00000400908.7	NP_001036146.1
RERE	NM_012102.4	c.3466G>T	p.Gly1156Trp	missense_variant	20/24		NP_036234.3
RERE	NM_001042682.2	c.1804G>T	p.Gly602Trp	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>T	p.Gly1156Trp	missense_variant	19/23	1	NM_001042681.2	ENSP00000383700.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Breda Genetics srl

Sep 15, 2020

The variant c.3466G>T (p.Gly1156Trp) in the RERE gene has not been reported in dbSNP, gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP) or ClinVar. The nucleotide position is highly conserved across 35 mammalian species (GERP RS: 5.56). In silico analysis indicates that the variant might be damaging. Another de novo pathogenic missense variant, affecting the same nucleotide position, c.3466G>A (p.Gly1156Arg), has been reported by Fregeau et al. (2016) in a child with intrauterine growth retardation, global developmental delay, mild spastic quadriparesis, dysarthric speech, swallowing difficulties, bilateral optic colobomas and other eye abnormalities, mild sensorineural hearing loss, and brain MRI abnormalities (PMID: 27087320). Based on ACMG variant interpretation guidelines, we classify this variant as uncertain. However, based on the aforementioned evidence, there is a given likelihood that the variant may actually be pathogenic, even if we cannot exclude that it is a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.3	M;.;.;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.024	D;T;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.61
MutPred		0.50		Gain of catalytic residue at L1154 (P = 0.0101);.;.;Gain of catalytic residue at L1154 (P = 0.0101);
MVP		0.64
MPC		0.42
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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;