rs1351965

Variant names:

• chr3-142404542-A-G
• rs1351965
• NM_001282857.2:c.1883+365T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282857.2(XRN1):​c.1883+365T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,110 control chromosomes in the GnomAD database, including 43,683 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 0.75 (43683 hom., cov: 31)
• Consequence: XRN1 NM_001282857.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.209
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRN1	NM_001282857.2	c.1883+365T>C		intron_variant	Intron 16 of 40	ENST00000392981.7	NP_001269786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRN1	ENST00000392981.7	c.1883+365T>C		intron_variant	Intron 16 of 40	1	NM_001282857.2	ENSP00000376707.2
XRN1	ENST00000264951.8	c.1883+365T>C		intron_variant	Intron 16 of 41	1		ENSP00000264951.4
XRN1	ENST00000498077.6	c.278+365T>C		intron_variant	Intron 2 of 26	5		ENSP00000419683.2
XRN1	ENST00000472697.5	n.1474+365T>C		intron_variant	Intron 13 of 20	2

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113745 AN: 151992 Hom.: 43620 Cov.: 31

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.747

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

GnomAD4 genome AF: 0.749 AC: 113864 AN: 152110 Hom.: 43683 Cov.: 31 AF XY: 0.747 AC XY: 55516 AN XY: 74342

African (AFR) AF: 0.921 AC: 38249 AN: 41530

American (AMR) AF: 0.738 AC: 11274 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2547 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3212 AN: 5172

South Asian (SAS) AF: 0.505 AC: 2431 AN: 4810

European-Finnish (FIN) AF: 0.727 AC: 7686 AN: 10572

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45900 AN: 67962

Other (OTH) AF: 0.751 AC: 1584 AN: 2110

Alfa AF: 0.702 Hom.: 53794

Bravo AF: 0.762

Asia WGS AF: 0.597 AC: 2076 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.9
DANN	Benign	0.47
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1351965; hg19: chr3-142123384;