Variant 3-142312732-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001282857.2(XRN1):c.4648C>A(p.Leu1550Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,459,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

XRN1
NM_001282857.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.379

Variant links:

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]

XRN1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05804637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRN1	NM_001282857.2 linkuse as main transcript	c.4648C>A	p.Leu1550Ile	missense_variant	40/41	ENST00000392981.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRN1	ENST00000392981.7 linkuse as main transcript	c.4648C>A	p.Leu1550Ile	missense_variant	40/41	1	NM_001282857.2	P3	Q8IZH2-2
XRN1	ENST00000264951.8 linkuse as main transcript	c.4684C>A	p.Leu1562Ile	missense_variant	41/42	1		A2	Q8IZH2-1
XRN1	ENST00000498077.6 linkuse as main transcript	c.3046C>A	p.Leu1016Ile	missense_variant	26/27	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1459656

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726206

show subpopulations

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:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.4684C>A (p.L1562I) alteration is located in exon 41 (coding exon 41) of the XRN1 gene. This alteration results from a C to A substitution at nucleotide position 4684, causing the leucine (L) at amino acid position 1562 to be replaced by an isoleucine (I). 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

Benign

0.065

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.061

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.037

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

N;.

MutationTaster

Benign

0.93

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.061

Sift

Benign

0.23

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0010

B;B

Vest4

0.22

MutPred

0.12

Loss of glycosylation at S1560 (P = 0.1084);.;

MVP

0.043

MPC

0.23

ClinPred

0.33

GERP RS

4.2

Varity_R

0.070

gMVP

0.12

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over