Genetic Variant ZRSR2:p.Arg182Lys (chrX-15809306-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005089.4(ZRSR2):c.545G>A(p.Arg182Lys) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.44

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4 link	c.545G>A	p.Arg182Lys	missense_variant	Exon 7 of 11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 link	c.614G>A	p.Arg205Lys	missense_variant	Exon 6 of 10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZRSR2	ENST00000307771.8 link	c.545G>A	p.Arg182Lys	missense_variant	Exon 7 of 11	1	NM_005089.4	ENSP00000303015.7	Q15696
ZRSR2	ENST00000684799.1 link	c.467G>A	p.Arg156Lys	missense_variant	Exon 6 of 11			ENSP00000510773.1	A0A8I5KSD0
ZRSR2	ENST00000690252.1 link	n.545G>A		non_coding_transcript_exon_variant	Exon 7 of 13			ENSP00000510140.1	A0A8I5KRH1
ZRSR2	ENST00000691502.1 link	n.545G>A		non_coding_transcript_exon_variant	Exon 7 of 13			ENSP00000509336.1	A0A8I5QKS0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000557

AC:

AN:

179444

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000186

AC:

AN:

1073877

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

340593

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25922

American (AMR)

AF:

0.00

AC:

AN:

34740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19139

East Asian (EAS)

AF:

0.00

AC:

AN:

30081

South Asian (SAS)

AF:

0.00

AC:

AN:

52844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4069

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

821269

Other (OTH)

AF:

0.0000221

AC:

AN:

45319

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.545G>A (p.R182K) alteration is located in exon 7 (coding exon 7) of the ZRSR2 gene. This alteration results from a G to A substitution at nucleotide position 545, causing the arginine (R) at amino acid position 182 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.8

PhyloP100

9.4

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.78

Gain of methylation at R182 (P = 0.0073);

MVP

0.81

MPC

1.2

ClinPred

0.99

GERP RS

5.3

Varity_R

0.93

gMVP

0.96

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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X-15809306-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over