X-15820247-C-T

Position:

• chrX-15820247-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005089.4(ZRSR2):​c.868C>T​(p.Arg290*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZRSR2 NM_005089.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.07

Genes affected

ZRSR2 (HGNC:23019): (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) This gene encodes an essential splicing factor. The encoded protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3' splice site in pre-mRNA splicing, and may play a role in network interactions during spliceosome assembly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-15820247-C-T is Pathogenic according to our data. Variant chrX-15820247-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3341112.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZRSR2	NM_005089.4	c.868C>T	p.Arg290*	stop_gained	10/11	ENST00000307771.8	NP_005080.1
ZRSR2	XM_011545589.4	c.937C>T	p.Arg313*	stop_gained	9/10		XP_011543891.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8	c.868C>T	p.Arg290*	stop_gained	10/11	1	NM_005089.4	ENSP00000303015.7
ZRSR2	ENST00000684799.1	c.790C>T	p.Arg264*	stop_gained	9/11			ENSP00000510773.1
ZRSR2	ENST00000690252.1	n.868C>T		non_coding_transcript_exon_variant	10/13			ENSP00000510140.1
ZRSR2	ENST00000691502.1	n.868C>T		non_coding_transcript_exon_variant	10/13			ENSP00000509336.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

Mar 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
Vest4		0.95
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chrX-15838370; COSMIC: COSV57067798;