1-8355567-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001042681.2(RERE):c.4519A>G(p.Ile1507Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,598,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RERE NM_001042681.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.75

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17993486).
• BP6: Variant 1-8355567-T-C is Benign according to our data. Variant chr1-8355567-T-C is described in ClinVar as [Benign]. Clinvar id is 2150683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000201 (291/1446790) while in subpopulation NFE AF= 0.000248 (274/1103056). AF 95% confidence interval is 0.000224. There are 0 homozygotes in gnomad4_exome. There are 143 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RERE	NM_001042681.2	c.4519A>G	p.Ile1507Val	missense_variant	22/23	ENST00000400908.7
RERE	NM_012102.4	c.4519A>G	p.Ile1507Val	missense_variant	23/24
RERE	NM_001042682.2	c.2857A>G	p.Ile953Val	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RERE	ENST00000400908.7	c.4519A>G	p.Ile1507Val	missense_variant	22/23	1	NM_001042681.2	P1

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151414 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.0000734 AC: 17 AN: 231612 Hom.: 0 AF XY: 0.000110 AC XY: 14 AN XY: 127068

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 291 AN: 1446790 Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 143 AN XY: 717680

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151414 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73946

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000581 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M;.
MutationTaster	Benign	0.99	D;D;D;D;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D;T;D;D;D
Sift4G	Uncertain	0.0080	D;T;T;D;D;.
Polyphen		0.85	P;.;.;.;P;.
Vest4		0.36
MVP		0.40
MPC		0.30
ClinPred		0.13	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.49

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: rs146159811; hg19: chr1-8415627;