Variant X-15822920-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005089.4(ZRSR2):c.1127G>A(p.Arg376Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,211,263 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 77 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 11 hem., cov: 24)

Exomes 𝑓: 0.000089 ( 0 hom. 66 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01031363).

BS2

High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZRSR2	NM_005089.4 linkuse as main transcript	c.1127G>A	p.Arg376Lys	missense_variant	11/11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 linkuse as main transcript	c.1196G>A	p.Arg399Lys	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.1127G>A	p.Arg376Lys	missense_variant	11/11	1	NM_005089.4	ENSP00000303015.7	Q15696
ZRSR2	ENST00000684799.1 linkuse as main transcript	c.1049G>A	p.Arg350Lys	missense_variant	10/11			ENSP00000510773.1	A0A8I5KSD0
ZRSR2	ENST00000690252.1 linkuse as main transcript	n.1127G>A		non_coding_transcript_exon_variant	11/13			ENSP00000510140.1	A0A8I5KRH1
ZRSR2	ENST00000691502.1 linkuse as main transcript	n.1013G>A		non_coding_transcript_exon_variant	11/13			ENSP00000509336.1	A0A8I5QKS0

Frequencies

GnomAD3 genomes

AF:

0.000124

AC:

AN:

112964

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

AN XY:

35096

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:

0.00

Gnomad SAS

AF:

0.00504

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000196

AC:

AN:

183444

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

67912

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 SAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000892

AC:

AN:

1098245

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

AN XY:

363601

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000124

AC:

AN:

113018

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

AN XY:

35160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00505

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.000181

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

Jul 02, 2024

The c.1127G>A (p.R376K) alteration is located in exon 11 (coding exon 11) of the ZRSR2 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the arginine (R) at amino acid position 376 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

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.91

REVEL

Benign

0.12

Sift

Benign

0.27

Sift4G

Benign

0.21

Polyphen

0.34

Vest4

0.037

MutPred

0.19

Gain of ubiquitination at R376 (P = 0.0085);

MVP

0.61

MPC

0.46

ClinPred

0.065

GERP RS

5.5

Varity_R

0.29

gMVP

0.60

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

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