rs3816805

Positions:

• chr3-142357217-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282857.2(XRN1):​c.3465-98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,060,390 control chromosomes in the GnomAD database, including 168,548 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (31099 hom., cov: 31)
  • Exomes 𝑓: 0.55 (137449 hom.)
• Consequence: XRN1 NM_001282857.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

Genes affected

XRN1 (HGNC:30654): (5'-3' exoribonuclease 1) This gene encodes a member of the 5'-3' exonuclease family. The encoded protein may be involved in replication-dependent histone mRNA degradation, and interacts directly with the enhancer of mRNA-decapping protein 4. In addition to mRNA metabolism, a similar protein in yeast has been implicated in a variety of nuclear and cytoplasmic functions, including homologous recombination, meiosis, telomere maintenance, and microtubule assembly. Mutations in this gene are associated with osteosarcoma, suggesting that the encoded protein may also play a role in bone formation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRN1	NM_001282857.2	c.3465-98T>C		intron_variant		ENST00000392981.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRN1	ENST00000392981.7	c.3465-98T>C		intron_variant		1	NM_001282857.2	P3
XRN1	ENST00000264951.8	c.3465-98T>C		intron_variant		1		A2
XRN1	ENST00000498077.6	c.1861-98T>C		intron_variant		5
XRN1	ENST00000467077.1	n.365-98T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94710 AN: 151870 Hom.: 31037 Cov.: 31

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.545 AC: 495309 AN: 908402 Hom.: 137449 AF XY: 0.540 AC XY: 248917 AN XY: 461310

Gnomad4 AFR exome AF: 0.859

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.520

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.624 AC: 94821 AN: 151988 Hom.: 31099 Cov.: 31 AF XY: 0.618 AC XY: 45878 AN XY: 74274

Gnomad4 AFR AF: 0.845

Gnomad4 AMR AF: 0.523

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.618

Alfa AF: 0.564 Hom.: 23915

Bravo AF: 0.633

Asia WGS AF: 0.478 AC: 1662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.34

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: rs3816805; hg19: chr3-142076059;