9-133407871-G-T

Variant names:

• chr9-133407871-G-T
• rs781965721
• NM_020385.4:c.1085C>A

Variant summary

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

The NM_020385.4(REXO4):​c.1085C>A​(p.Pro362Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: REXO4 NM_020385.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99

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 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	c.1085C>A	p.Pro362Gln	missense_variant	Exon 7 of 8	ENST00000371942.8	NP_065118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REXO4	ENST00000371942.8	c.1085C>A	p.Pro362Gln	missense_variant	Exon 7 of 8	1	NM_020385.4	ENSP00000361010.3
REXO4	ENST00000371935.6	c.569C>A	p.Pro190Gln	missense_variant	Exon 5 of 6	3		ENSP00000361003.2
REXO4	ENST00000454825.1	c.569C>A	p.Pro190Gln	missense_variant	Exon 5 of 6	3		ENSP00000394229.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461360 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000195 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.013	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.56
MutPred		0.46		.;Loss of glycosylation at P362 (P = 0.0416);.;
MVP		0.48
MPC		0.78
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.68

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

Other links and lift over

dbSNP: rs781965721; hg19: chr9-136272995;