X-15790518-C-A

Variant names:

• chrX-15790518-C-A
• NM_005089.4:c.23C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005089.4(ZRSR2):​c.23C>A​(p.Thr8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.218

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057759225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 11	ENST00000307771.8	NP_005080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 11	1	NM_005089.4	ENSP00000303015.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1046911 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 339413

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>A (p.T8K) alteration is located in exon 1 (coding exon 1) of the ZRSR2 gene. This alteration results from a C to A substitution at nucleotide position 23, causing the threonine (T) at amino acid position 8 to be replaced by a lysine (K). 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	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.48
DEOGEN2	Benign	0.013	.;T
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.0070
Sift	Benign	0.58	.;T
Sift4G	Benign	0.073	T;T
Polyphen		0.012	.;B
Vest4		0.089
MutPred		0.21		Loss of phosphorylation at T8 (P = 0.0099);Loss of phosphorylation at T8 (P = 0.0099);
MVP		0.068
MPC		0.49
ClinPred		0.063	T
GERP RS		-1.6
Varity_R		0.042
gMVP		0.17

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: chrX-15808641;