Variant X-15823135-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005089.4(ZRSR2):c.1342C>T(p.Arg448Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,204,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 7 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.450

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073922336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZRSR2	NM_005089.4 linkuse as main transcript	c.1342C>T	p.Arg448Cys	missense_variant	11/11	ENST00000307771.8
ZRSR2	XM_011545589.4 linkuse as main transcript	c.1411C>T	p.Arg471Cys	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZRSR2	ENST00000307771.8 linkuse as main transcript	c.1342C>T	p.Arg448Cys	missense_variant	11/11	1	NM_005089.4	P2
ZRSR2	ENST00000684799.1 linkuse as main transcript	c.1264C>T	p.Arg422Cys	missense_variant	10/11			A2
ZRSR2	ENST00000690252.1 linkuse as main transcript	c.1342C>T	p.Arg448Cys	missense_variant, NMD_transcript_variant	11/13
ZRSR2	ENST00000691502.1 linkuse as main transcript	c.1228C>T	p.Arg410Cys	missense_variant, NMD_transcript_variant	11/13

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34132

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000667

GnomAD3 exomes

AF:

0.0000118

AC:

AN:

168885

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

60451

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000136

Gnomad OTH exome

AF:

0.000238

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1092173

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

359673

show subpopulations

Gnomad4 AFR exome

AF:

0.0000381

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.0000437

GnomAD4 genome

AF:

0.0000357

AC:

AN:

111913

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34191

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000658

Bravo

AF:

0.00000378

ExAC

AF:

0.0000421

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

Aug 17, 2022

The c.1342C>T (p.R448C) alteration is located in exon 11 (coding exon 11) of the ZRSR2 gene. This alteration results from a C to T substitution at nucleotide position 1342, causing the arginine (R) at amino acid position 448 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

Benign

-0.36

BayesDel_noAF

Benign

-0.75

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.52

M_CAP

Benign

0.0044

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.062

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0050

Polyphen

0.0

Vest4

0.17

MutPred

0.37

Loss of methylation at R448 (P = 0.018);

MVP

0.043

MPC

0.56

ClinPred

0.24

GERP RS

-0.38

Varity_R

0.18

gMVP

0.48

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