chr9-133407069-G-C

Position:

• chr9-133407069-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020385.4(REXO4):​c.1153C>G​(p.Gln385Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: REXO4 NM_020385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38997254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REXO4	NM_020385.4	c.1153C>G	p.Gln385Glu	missense_variant	Exon 8 of 8	ENST00000371942.8	NP_065118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REXO4	ENST00000371942.8	c.1153C>G	p.Gln385Glu	missense_variant	Exon 8 of 8	1	NM_020385.4	ENSP00000361010.3
REXO4	ENST00000371935.6	c.637C>G	p.Gln213Glu	missense_variant	Exon 6 of 6	3		ENSP00000361003.2
REXO4	ENST00000454825.1	c.637C>G	p.Gln213Glu	missense_variant	Exon 6 of 6	3		ENSP00000394229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.1153C>G (p.Q385E) alteration is located in exon 8 (coding exon 8) of the REXO4 gene. This alteration results from a C to G substitution at nucleotide position 1153, causing the glutamine (Q) at amino acid position 385 to be replaced by a glutamic acid (E). 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	0.086
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.3	.;N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.87	T;T;T
Sift4G	Benign	0.58	T;T;.
Polyphen		0.022	B;B;.
Vest4		0.20
MutPred		0.72		.;Loss of MoRF binding (P = 0.0725);.;
MVP		0.19
MPC		0.28
ClinPred		0.75	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.52

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: rs929644560; hg19: chr9-136272193;