Genetic Variant ZRSR2:p.Glu60Lys (chrX-15799928-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005089.4(ZRSR2):c.178G>A(p.Glu60Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,067 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33512053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4 link	c.178G>A	p.Glu60Lys	missense_variant	Exon 3 of 11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 link	c.247G>A	p.Glu83Lys	missense_variant	Exon 2 of 10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8 link	c.178G>A	p.Glu60Lys	missense_variant	Exon 3 of 11	1	NM_005089.4	ENSP00000303015.7		Q15696

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089067

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

355131

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26201

American (AMR)

AF:

0.00

AC:

AN:

34970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19241

East Asian (EAS)

AF:

0.00

AC:

AN:

30007

South Asian (SAS)

AF:

0.00

AC:

AN:

53183

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835162

Other (OTH)

AF:

0.00

AC:

AN:

45783

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

Jun 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.178G>A (p.E60K) alteration is located in exon 3 (coding exon 3) of the ZRSR2 gene. This alteration results from a G to A substitution at nucleotide position 178, causing the glutamic acid (E) at amino acid position 60 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

0.085

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

.;T

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.41

T;D

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.8

.;M

PhyloP100

3.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.75

N;N

REVEL

Benign

0.18

Sift

Benign

0.12

.;T

Sift4G

Benign

0.35

T;T

Polyphen

0.99

.;D

Vest4

0.33

MutPred

0.27

Gain of ubiquitination at E60 (P = 0.0051);Gain of ubiquitination at E60 (P = 0.0051);

MVP

0.83

MPC

0.46

ClinPred

0.91

GERP RS

5.0

Varity_R

0.59

gMVP

0.28

Mutation Taster

=77/23

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

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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