1-8358238-G-A

Variant names:

• chr1-8358238-G-A
• rs1553154132
• NM_001042681.2:c.4297C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001042681.2(RERE):​c.4297C>T​(p.His1433Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1433D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97
• Publications: 0 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 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001042681.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-8358238-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521311.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 1-8358238-G-A is Pathogenic according to our data. Variant chr1-8358238-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1686749.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	NM_001042681.2	MANE Select	c.4297C>T	p.His1433Tyr	missense	Exon 20 of 23	NP_001036146.1
	RERE	NM_012102.4		c.4297C>T	p.His1433Tyr	missense	Exon 21 of 24	NP_036234.3
	RERE	NM_001042682.2		c.2635C>T	p.His879Tyr	missense	Exon 10 of 13	NP_001036147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERE	ENST00000400908.7	TSL:1 MANE Select	c.4297C>T	p.His1433Tyr	missense	Exon 20 of 23	ENSP00000383700.2
	RERE	ENST00000337907.7	TSL:1	c.4297C>T	p.His1433Tyr	missense	Exon 21 of 24	ENSP00000338629.3
	RERE	ENST00000476556.5	TSL:1	c.2635C>T	p.His879Tyr	missense	Exon 10 of 13	ENSP00000422246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.74	P
Vest4		0.87
MutPred		0.71		Gain of phosphorylation at H1433 (P = 0.0534)
MVP		0.91
MPC		0.41
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.88
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs1553154132; hg19: chr1-8418298;