3-142312732-G-T

Position:

• chr3-142312732-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05804637).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRN1	NM_001282857.2	c.4648C>A	p.Leu1550Ile	missense_variant	40/41	ENST00000392981.7	NP_001269786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRN1	ENST00000392981.7	c.4648C>A	p.Leu1550Ile	missense_variant	40/41	1	NM_001282857.2	ENSP00000376707	P3
XRN1	ENST00000264951.8	c.4684C>A	p.Leu1562Ile	missense_variant	41/42	1		ENSP00000264951	A2
XRN1	ENST00000498077.6	c.3046C>A	p.Leu1016Ile	missense_variant	26/27	5		ENSP00000419683

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459656 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726206

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.43	T
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	T
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.

Other links and lift over

hg19: chr3-142031574;