19-1816257-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020695.4(REXO1):c.3545C>A(p.Ala1182Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: REXO1 NM_020695.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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]

MIR1909 (HGNC:35393): (microRNA 1909) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REXO1	NM_020695.4	c.3545C>A	p.Ala1182Asp	missense_variant	15/16	ENST00000170168.9
MIR1909	NR_031730.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REXO1	ENST00000170168.9	c.3545C>A	p.Ala1182Asp	missense_variant	15/16	1	NM_020695.4	P2
MIR1909	ENST00000411312.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437120 Hom.: 0 Cov.: 39 AF XY: 0.00000561 AC XY: 4 AN XY: 712572

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: 0.00000364

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

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

Aug 21, 2023

The c.3545C>A (p.A1182D) alteration is located in exon 15 (coding exon 15) of the REXO1 gene. This alteration results from a C to A substitution at nucleotide position 3545, causing the alanine (A) at amino acid position 1182 to be replaced by an aspartic acid (D). 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	0.99
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Benign	0.24
Sift	Benign	0.033	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.56		Loss of MoRF binding (P = 0.0663);.;
MVP		0.17
MPC		0.60
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.63
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1816256;