Variant X-15822833-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005089.4(ZRSR2):c.1040A>G(p.Tyr347Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,211,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33867168).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZRSR2	NM_005089.4 linkuse as main transcript	c.1040A>G	p.Tyr347Cys	missense_variant	11/11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 linkuse as main transcript	c.1109A>G	p.Tyr370Cys	missense_variant	10/10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZRSR2	ENST00000307771.8 linkuse as main transcript	c.1040A>G	p.Tyr347Cys	missense_variant	11/11	1	NM_005089.4	ENSP00000303015.7	Q15696
ZRSR2	ENST00000684799.1 linkuse as main transcript	c.962A>G	p.Tyr321Cys	missense_variant	10/11			ENSP00000510773.1	A0A8I5KSD0
ZRSR2	ENST00000690252.1 linkuse as main transcript	n.1040A>G		non_coding_transcript_exon_variant	11/13			ENSP00000510140.1	A0A8I5KRH1
ZRSR2	ENST00000691502.1 linkuse as main transcript	n.938-12A>G		intron_variant				ENSP00000509336.1	A0A8I5QKS0

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112786

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34928

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183523

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67949

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098266

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112839

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34991

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1040A>G (p.Y347C) alteration is located in exon 11 (coding exon 11) of the ZRSR2 gene. This alteration results from a A to G substitution at nucleotide position 1040, causing the tyrosine (Y) at amino acid position 347 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

0.083

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

M_CAP

Benign

0.057

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.31

Sift

Uncertain

0.024

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.45

MutPred

0.48

Gain of catalytic residue at L348 (P = 0.0125);

MVP

0.55

MPC

0.54

ClinPred

0.51

GERP RS

5.3

Varity_R

0.26

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over