Genetic Variant NM_020385.4:c.1049A>G (chr9-133408793-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020385.4(REXO4):c.1049A>G(p.Tyr350Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,597,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

REXO4
NM_020385.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REXO4	NM_020385.4 link	c.1049A>G	p.Tyr350Cys	missense_variant	Exon 6 of 8	ENST00000371942.8	NP_065118.2	Q9GZR2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
REXO4	ENST00000371942.8 link	c.1049A>G	p.Tyr350Cys	missense_variant	Exon 6 of 8	1	NM_020385.4	ENSP00000361010.3	Q9GZR2-1
REXO4	ENST00000371935.6 link	c.533A>G	p.Tyr178Cys	missense_variant	Exon 4 of 6	3		ENSP00000361003.2	Q9GZR2-2
REXO4	ENST00000454825.1 link	c.533A>G	p.Tyr178Cys	missense_variant	Exon 4 of 6	3		ENSP00000394229.1	A0A0C4DG31

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249952

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135308

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1445466

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720368

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1049A>G (p.Y350C) alteration is located in exon 6 (coding exon 6) of the REXO4 gene. This alteration results from a A to G substitution at nucleotide position 1049, causing the tyrosine (Y) at amino acid position 350 to be replaced by a cysteine (C). 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

Uncertain

0.44

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

.;T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-8.8

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.015

D;D;D

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

0.75

P;D;.

Vest4

0.50

MutPred

0.53

.;Gain of methylation at K349 (P = 0.0125);.;

MVP

0.59

MPC

0.79

ClinPred

0.96

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.71

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

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