dbSNP rs368125859: ZRSR2:p.Glu85Ala (chrX-15803738-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005089.4(ZRSR2):c.254A>C(p.Glu85Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000075 in 1,199,910 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 0.000045 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046478957).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4 link	c.254A>C	p.Glu85Ala	missense_variant	Exon 4 of 11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 link	c.323A>C	p.Glu108Ala	missense_variant	Exon 3 of 10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8 link	c.254A>C	p.Glu85Ala	missense_variant	Exon 4 of 11	1	NM_005089.4	ENSP00000303015.7		Q15696

Frequencies

GnomAD3 genomes

AF:

0.0000451

AC:

AN:

110934

Hom.:

Cov.:

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:

0.00140

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

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

165742

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:

0.000155

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1088923

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

356101

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26196

American (AMR)

AF:

0.00

AC:

AN:

34318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19235

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29942

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52503

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836777

Other (OTH)

AF:

0.0000437

AC:

AN:

45792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000451

AC:

AN:

110987

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

33173

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30551

American (AMR)

AF:

0.00

AC:

AN:

10259

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00140

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2637

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5857

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53056

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.254A>C (p.E85A) alteration is located in exon 4 (coding exon 4) of the ZRSR2 gene. This alteration results from a A to C substitution at nucleotide position 254, causing the glutamic acid (E) at amino acid position 85 to be replaced by an alanine (A). 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

0.097

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

M_CAP

Benign

0.011

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

4.1

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.14

Sift

Benign

0.030

Sift4G

Uncertain

0.054

Polyphen

0.23

Vest4

0.27

MutPred

0.15

Gain of MoRF binding (P = 0.0587);

MVP

0.31

MPC

0.43

ClinPred

0.98

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.66

gMVP

0.36

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs368125859

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