19-1816766-G-C

Variant summary

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

The NM_020695.4(REXO1):c.3249C>G(p.Asp1083Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: REXO1 NM_020695.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

Genes affected

REXO1 (HGNC:24616): (RNA exonuclease 1 homolog) Predicted to enable exonuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. Located in nuclear body. [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/exons	MANE	UniProt
REXO1	NM_020695.4	c.3249C>G	p.Asp1083Glu	missense_variant	13/16	ENST00000170168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REXO1	ENST00000170168.9	c.3249C>G	p.Asp1083Glu	missense_variant	13/16	1	NM_020695.4	P2
REXO1	ENST00000643515.1	c.1176C>G	p.Asp392Glu	missense_variant	9/12			A2
REXO1	ENST00000590936.5	c.*273C>G		3_prime_UTR_variant, NMD_transcript_variant	7/10	5
REXO1	ENST00000586291.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Apr 25, 2023

The c.3249C>G (p.D1083E) alteration is located in exon 13 (coding exon 13) of the REXO1 gene. This alteration results from a C to G substitution at nucleotide position 3249, causing the aspartic acid (D) at amino acid position 1083 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	Pathogenic	0.88
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.039
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		0.99	D;.
Vest4		0.61
MutPred		0.73		Gain of sheet (P = 0.1539);.;
MVP		0.54
MPC		0.38
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.72

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: rs2069377506; hg19: chr19-1816765;