Variant 9-133417752-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020385.4(REXO4):c.93C>G(p.Asn31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

REXO4
NM_020385.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.142

Variant links:

Genes affected

REXO4 (HGNC:12820): (REX4 homolog, 3'-5' exonuclease) Enables DNA binding activity and nuclease activity. Involved in DNA catabolic process, endonucleolytic; DNA catabolic process, exonucleolytic; and DNA repair. Located in nuclear speck and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

REXO4 links:

ADAMTS13 (HGNC:1366): (ADAM metallopeptidase with thrombospondin type 1 motif 13) This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ADAMTS13 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018180221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REXO4	NM_020385.4 linkuse as main transcript	c.93C>G	p.Asn31Lys	missense_variant	1/8	ENST00000371942.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REXO4	ENST00000371942.8 linkuse as main transcript	c.93C>G	p.Asn31Lys	missense_variant	1/8	1	NM_020385.4	P1	Q9GZR2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250746

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135624

show subpopulations

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461120

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.93C>G (p.N31K) alteration is located in exon 1 (coding exon 1) of the REXO4 gene. This alteration results from a C to G substitution at nucleotide position 93, causing the asparagine (N) at amino acid position 31 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.7

DANN

Benign

0.81

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.16

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.77

T;T;.

Polyphen

0.0010

B;B;.

Vest4

0.11

MutPred

0.19

Gain of methylation at N31 (P = 0.01);Gain of methylation at N31 (P = 0.01);Gain of methylation at N31 (P = 0.01);

MVP

0.076

MPC

0.25

ClinPred

0.013

GERP RS

-1.8

Varity_R

0.040

gMVP

0.039

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over