X-15822999-CAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005089.4(ZRSR2):c.1207_1208del(p.Arg403GlyfsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000911 in 1,098,251 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZRSR2 NM_005089.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.73

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.167 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-15822999-CAG-C is Pathogenic according to our data. Variant chrX-15822999-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978620.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZRSR2	NM_005089.4	c.1207_1208del	p.Arg403GlyfsTer24	frameshift_variant	11/11	ENST00000307771.8
ZRSR2	XM_011545589.4	c.1276_1277del	p.Arg426GlyfsTer24	frameshift_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZRSR2	ENST00000307771.8	c.1207_1208del	p.Arg403GlyfsTer24	frameshift_variant	11/11	1	NM_005089.4	P2
ZRSR2	ENST00000684799.1	c.1129_1130del	p.Arg377GlyfsTer24	frameshift_variant	10/11			A2
ZRSR2	ENST00000690252.1	c.1207_1208del	p.Arg403GlyfsTer24	frameshift_variant, NMD_transcript_variant	11/13
ZRSR2	ENST00000691502.1	c.1093_1094del	p.Arg365GlyfsTer24	frameshift_variant, NMD_transcript_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098251 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 363605

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly sequence;C2750604:Median cleft lip and palate;C3278123:Severe hydrocephalus;CN130023:Heart, malformation of Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Reproductive Medicine, Peking University Third Hospital

Oct 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1933151965; hg19: chrX-15841122;