rs3816805

Variant names:

• chr3-142357217-A-G
• rs3816805
• NM_001282857.2:c.3465-98T>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.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
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282857.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRN1	NM_001282857.2	MANE Select	c.3465-98T>C		intron	N/A	NP_001269786.1
	XRN1	NM_019001.5		c.3465-98T>C		intron	N/A	NP_061874.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRN1	ENST00000392981.7	TSL:1 MANE Select	c.3465-98T>C		intron	N/A	ENSP00000376707.2
	XRN1	ENST00000264951.8	TSL:1	c.3465-98T>C		intron	N/A	ENSP00000264951.4
	XRN1	ENST00000498077.6	TSL:5	c.1860-98T>C		intron	N/A	ENSP00000419683.2

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

African (AFR) AF: 0.859 AC: 18775 AN: 21850

American (AMR) AF: 0.470 AC: 14642 AN: 31170

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 10618 AN: 20400

East Asian (EAS) AF: 0.443 AC: 14692 AN: 33158

South Asian (SAS) AF: 0.398 AC: 25212 AN: 63348

European-Finnish (FIN) AF: 0.547 AC: 24874 AN: 45454

Middle Eastern (MID) AF: 0.536 AC: 2028 AN: 3784

European-Non Finnish (NFE) AF: 0.558 AC: 361484 AN: 647704

Other (OTH) AF: 0.553 AC: 22984 AN: 41534

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

African (AFR) AF: 0.845 AC: 35049 AN: 41456

American (AMR) AF: 0.523 AC: 7983 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1792 AN: 3470

East Asian (EAS) AF: 0.464 AC: 2394 AN: 5162

South Asian (SAS) AF: 0.407 AC: 1961 AN: 4818

European-Finnish (FIN) AF: 0.539 AC: 5671 AN: 10528

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37882 AN: 67958

Other (OTH) AF: 0.618 AC: 1307 AN: 2114

Alfa AF: 0.574 Hom.: 32602

Bravo AF: 0.633

Asia WGS AF: 0.478 AC: 1662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.34
PhyloP100		1.0
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: rs3816805; hg19: chr3-142076059; COSMIC: COSV107298427;