3-142311795-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001282857.2(XRN1):c.4801G>A(p.Ala1601Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000032 in 1,592,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
XRN1
NM_001282857.2 missense
NM_001282857.2 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 3.66
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21040061).
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRN1 | NM_001282857.2 | c.4801G>A | p.Ala1601Thr | missense_variant | 41/41 | ENST00000392981.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRN1 | ENST00000392981.7 | c.4801G>A | p.Ala1601Thr | missense_variant | 41/41 | 1 | NM_001282857.2 | P3 | |
XRN1 | ENST00000264951.8 | c.4837G>A | p.Ala1613Thr | missense_variant | 42/42 | 1 | A2 | ||
XRN1 | ENST00000498077.6 | c.3199G>A | p.Ala1067Thr | missense_variant | 27/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000128 AC: 3AN: 234160Hom.: 0 AF XY: 0.00000787 AC XY: 1AN XY: 127046
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GnomAD4 exome AF: 0.0000319 AC: 46AN: 1440094Hom.: 0 Cov.: 30 AF XY: 0.0000252 AC XY: 18AN XY: 715278
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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 | Jan 06, 2023 | The c.4837G>A (p.A1613T) alteration is located in exon 42 (coding exon 42) of the XRN1 gene. This alteration results from a G to A substitution at nucleotide position 4837, causing the alanine (A) at amino acid position 1613 to be replaced by a threonine (T). 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
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Benign
T;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at T1608 (P = 0.034);.;
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