Genetic Variant ZRSR2:p.Leu237Gln (chrX-15815829-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005089.4(ZRSR2):c.710T>A(p.Leu237Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000091 in 1,208,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 2 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.98

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: Likely_benign. The variant received -4 ACMG points.

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.710T>A	p.Leu237Gln	missense_variant	Exon 8 of 11	ENST00000307771.8	NP_005080.1	Q15696
ZRSR2	XM_011545589.4 link	c.779T>A	p.Leu260Gln	missense_variant	Exon 7 of 10		XP_011543891.3	A0A8I5KSD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZRSR2	ENST00000307771.8 link	c.710T>A	p.Leu237Gln	missense_variant	Exon 8 of 11	1	NM_005089.4	ENSP00000303015.7	Q15696
ZRSR2	ENST00000684799.1 link	c.632T>A	p.Leu211Gln	missense_variant	Exon 7 of 11			ENSP00000510773.1	A0A8I5KSD0
ZRSR2	ENST00000690252.1 link	n.710T>A		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000510140.1	A0A8I5KRH1
ZRSR2	ENST00000691502.1 link	n.710T>A		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000509336.1	A0A8I5QKS0

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111310

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182284

AF XY:

0.0000150

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1097409

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362785

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26374

American (AMR)

AF:

0.00

AC:

AN:

35072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19323

East Asian (EAS)

AF:

0.00

AC:

AN:

30187

South Asian (SAS)

AF:

0.00

AC:

AN:

53968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

841792

Other (OTH)

AF:

0.0000869

AC:

AN:

46053

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30576

American (AMR)

AF:

0.00

AC:

AN:

10433

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

2629

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5991

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53050

Other (OTH)

AF:

0.000670

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.710T>A (p.L237Q) alteration is located in exon 8 (coding exon 8) of the ZRSR2 gene. This alteration results from a T to A substitution at nucleotide position 710, causing the leucine (L) at amino acid position 237 to be replaced by a glutamine (Q). 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

0.15

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.022

MutationAssessor

Benign

1.7

PhyloP100

6.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.70

Sift

Benign

0.20

Sift4G

Benign

0.58

Polyphen

1.0

Vest4

0.59

MutPred

0.53

Gain of disorder (P = 0.0151);

MVP

0.89

MPC

0.92

ClinPred

0.83

GERP RS

4.2

Varity_R

0.64

gMVP

0.67

Mutation Taster

=81/19

polymorphism

(source)

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

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X-15815829-T-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