Genetic Variant NM_005089.4:c.656A>G (chrX-15815775-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005089.4(ZRSR2):c.656A>G(p.Tyr219Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,565 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.10

Publications

0 publications found

Variant links:

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]

ZRSR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4 link	c.656A>G	p.Tyr219Cys	missense_variant	Exon 8 of 11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 link	c.725A>G	p.Tyr242Cys	missense_variant	Exon 7 of 10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZRSR2	ENST00000307771.8 link	c.656A>G	p.Tyr219Cys	missense_variant	Exon 8 of 11	1	NM_005089.4	ENSP00000303015.7	Q15696
ZRSR2	ENST00000684799.1 link	c.578A>G	p.Tyr193Cys	missense_variant	Exon 7 of 11			ENSP00000510773.1	A0A8I5KSD0
ZRSR2	ENST00000690252.1 link	n.656A>G		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000510140.1	A0A8I5KRH1
ZRSR2	ENST00000691502.1 link	n.656A>G		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000509336.1	A0A8I5QKS0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097565

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362921

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841581

Other (OTH)

AF:

0.00

AC:

AN:

46066

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.656A>G (p.Y219C) alteration is located in exon 8 (coding exon 8) of the ZRSR2 gene. This alteration results from a A to G substitution at nucleotide position 656, causing the tyrosine (Y) at amino acid position 219 to be replaced by a cysteine (C). 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

0.25

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.7

PhyloP100

9.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.73

MutPred

0.31

Loss of phosphorylation at Y219 (P = 0.0647);

MVP

0.96

MPC

1.4

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.86

Mutation Taster

=54/46

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over