chr3-142318603-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001282857.2(XRN1):c.4610C>T(p.Pro1537Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000895 in 1,453,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000089 ( 0 hom. )
Consequence
XRN1
NM_001282857.2 missense
NM_001282857.2 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 3.65
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13819373).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRN1 | NM_001282857.2 | c.4610C>T | p.Pro1537Leu | missense_variant | 39/41 | ENST00000392981.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRN1 | ENST00000392981.7 | c.4610C>T | p.Pro1537Leu | missense_variant | 39/41 | 1 | NM_001282857.2 | P3 | |
XRN1 | ENST00000264951.8 | c.4607C>T | p.Pro1536Leu | missense_variant | 39/42 | 1 | A2 | ||
XRN1 | ENST00000498077.6 | c.3008C>T | p.Pro1003Leu | missense_variant | 25/27 | 5 | |||
XRN1 | ENST00000489241.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000841 AC: 2AN: 237750Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 127442
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000895 AC: 13AN: 1453186Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5AN XY: 721802
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GnomAD4 genome ? Cov.: 32
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?
Cov.:
32
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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 18, 2021 | The c.4607C>T (p.P1536L) alteration is located in exon 39 (coding exon 39) of the XRN1 gene. This alteration results from a C to T substitution at nucleotide position 4607, causing the proline (P) at amino acid position 1536 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
N;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Loss of disorder (P = 0.0109);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at