rs764639907

Variant names:

• chrX-15804159-G-A
• rs764639907
• NM_005089.4:c.361G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005089.4(ZRSR2):​c.361G>A​(p.Glu121Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000251 in 1,195,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000027 (0 hom. 18 hem.)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.123567045).
• BS2: High Hemizygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4	c.361G>A	p.Glu121Lys	missense_variant	Exon 5 of 11	ENST00000307771.8	NP_005080.1
ZRSR2	XM_011545589.4	c.430G>A	p.Glu144Lys	missense_variant	Exon 4 of 10		XP_011543891.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8	c.361G>A	p.Glu121Lys	missense_variant	Exon 5 of 11	1	NM_005089.4	ENSP00000303015.7
ZRSR2	ENST00000684799.1	c.283G>A	p.Glu95Lys	missense_variant	Exon 4 of 11			ENSP00000510773.1
ZRSR2	ENST00000690252.1	n.361G>A		non_coding_transcript_exon_variant	Exon 5 of 13			ENSP00000510140.1
ZRSR2	ENST00000691502.1	n.361G>A		non_coding_transcript_exon_variant	Exon 5 of 13			ENSP00000509336.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111173 Hom.: 0 Cov.: 22

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: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000650 AC: 11 AN: 169326 AF XY: 0.000174

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 29 AN: 1084800 Hom.: 0 Cov.: 28 AF XY: 0.0000511 AC XY: 18 AN XY: 352528

African (AFR) AF: 0.00 AC: 0 AN: 25836

American (AMR) AF: 0.00 AC: 0 AN: 32956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19028

East Asian (EAS) AF: 0.00 AC: 0 AN: 29932

South Asian (SAS) AF: 0.000558 AC: 29 AN: 52009

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40375

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835091

Other (OTH) AF: 0.00 AC: 0 AN: 45505

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111173 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33359

African (AFR) AF: 0.00 AC: 0 AN: 30637

American (AMR) AF: 0.00 AC: 0 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2685

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53061

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.0000572 Hom.: 1

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361G>A (p.E121K) alteration is located in exon 5 (coding exon 5) of the ZRSR2 gene. This alteration results from a G to A substitution at nucleotide position 361, causing the glutamic acid (E) at amino acid position 121 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	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.99	D
Vest4		0.12
MutPred		0.23		Gain of MoRF binding (P = 0.0089);
MVP		0.38
MPC		0.46
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.38
gMVP		0.55
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs764639907; hg19: chrX-15822282;