Genetic Variant NM_005089.4:c.17A>C (chrX-15790512-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.17A>C(p.Lys6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,158,629 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000029 ( 0 hom. 13 hem. )

Consequence

ZRSR2
NM_005089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.73

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0531635).

BS2

High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4 link	c.17A>C	p.Lys6Thr	missense_variant	Exon 1 of 11	ENST00000307771.8	NP_005080.1	Q15696

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8 link	c.17A>C	p.Lys6Thr	missense_variant	Exon 1 of 11	1	NM_005089.4	ENSP00000303015.7		Q15696

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111969

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1046660

Hom.:

Cov.:

AF XY:

0.0000383

AC XY:

AN XY:

339296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24173

American (AMR)

AF:

0.00

AC:

AN:

24820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18265

East Asian (EAS)

AF:

0.00

AC:

AN:

26808

South Asian (SAS)

AF:

0.00

AC:

AN:

48883

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37677

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4053

European-Non Finnish (NFE)

AF:

0.0000367

AC:

AN:

817935

Other (OTH)

AF:

0.00

AC:

AN:

44046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111969

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34153

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30861

American (AMR)

AF:

0.00

AC:

AN:

10643

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6117

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53063

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.17A>C (p.K6T) alteration is located in exon 1 (coding exon 1) of the ZRSR2 gene. This alteration results from a A to C substitution at nucleotide position 17, causing the lysine (K) at amino acid position 6 to be replaced by a threonine (T). 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

0.061

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.038

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.015

.;T

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.25

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L

PhyloP100

-2.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.025

Sift

Benign

0.46

.;T

Sift4G

Benign

0.42

T;T

Polyphen

0.0

.;B

Vest4

0.12

MutPred

0.17

Loss of ubiquitination at K6 (P = 0.0043);Loss of ubiquitination at K6 (P = 0.0043);

MVP

0.15

MPC

0.49

ClinPred

0.082

GERP RS

-11

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.074

gMVP

0.11

Mutation Taster

=95/5

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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NM_005089.4:c.17A>C

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