Genetic Variant NM_001042681.2:c.4591G>A (chr1-8355495-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001042681.2(RERE):c.4591G>A(p.Ala1531Thr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1531S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RERE
NM_001042681.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 publications found

Variant links:

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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

RERE links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	NM_001042681.2	MANE Select	c.4591G>A	p.Ala1531Thr	missense	Exon 22 of 23	NP_001036146.1	Q9P2R6-1
RERE	NM_012102.4		c.4591G>A	p.Ala1531Thr	missense	Exon 23 of 24	NP_036234.3
RERE	NM_001042682.2		c.2929G>A	p.Ala977Thr	missense	Exon 12 of 13	NP_001036147.1	Q9P2R6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RERE	ENST00000400908.7	TSL:1 MANE Select	c.4591G>A	p.Ala1531Thr	missense	Exon 22 of 23	ENSP00000383700.2	Q9P2R6-1
RERE	ENST00000337907.7	TSL:1	c.4591G>A	p.Ala1531Thr	missense	Exon 23 of 24	ENSP00000338629.3	Q9P2R6-1
RERE	ENST00000476556.5	TSL:1	c.2929G>A	p.Ala977Thr	missense	Exon 12 of 13	ENSP00000422246.1	Q9P2R6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.8

PhyloP100

7.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.90

MutPred

0.64

Gain of relative solvent accessibility (P = 0.09)

MVP

0.91

MPC

0.34

ClinPred

0.98

GERP RS

6.0

Varity_R

0.48

gMVP

0.66

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over