3-142395852-C-T

Variant summary

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

The NM_001282857.2(XRN1):c.2339+1477G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,042 control chromosomes in the GnomAD database, including 10,797 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 0.38 (10797 hom., cov: 32)
• Consequence: XRN1 NM_001282857.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409

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=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRN1	NM_001282857.2	c.2339+1477G>A		intron_variant		ENST00000392981.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRN1	ENST00000392981.7	c.2339+1477G>A		intron_variant		1	NM_001282857.2	P3
XRN1	ENST00000264951.8	c.2339+1477G>A		intron_variant		1		A2
XRN1	ENST00000498077.6	c.735+1477G>A		intron_variant		5
XRN1	ENST00000472697.5	n.1930+1477G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57202 AN: 151922 Hom.: 10783 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.400

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.376 AC: 57236 AN: 152042 Hom.: 10797 Cov.: 32 AF XY: 0.375 AC XY: 27905 AN XY: 74318

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.364

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.403

Alfa AF: 0.393 Hom.: 5631

Bravo AF: 0.375

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.8
Dann	Benign	0.67

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: rs7643377; hg19: chr3-142114694;