X-15822802-A-G

Variant names:

• chrX-15822802-A-G
• rs768331870
• NM_005089.4:c.1009A>G

Variant summary

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

The NM_005089.4(ZRSR2):​c.1009A>G​(p.Asn337Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,211,076 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 54 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 50 hem.)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.02
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4	c.1009A>G	p.Asn337Asp	missense_variant	Exon 11 of 11	ENST00000307771.8	NP_005080.1
ZRSR2	XM_011545589.4	c.1078A>G	p.Asn360Asp	missense_variant	Exon 10 of 10		XP_011543891.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8	c.1009A>G	p.Asn337Asp	missense_variant	Exon 11 of 11	1	NM_005089.4	ENSP00000303015.7
ZRSR2	ENST00000684799.1	c.931A>G	p.Asn311Asp	missense_variant	Exon 10 of 11			ENSP00000510773.1
ZRSR2	ENST00000690252.1	n.1009A>G		non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000510140.1
ZRSR2	ENST00000691502.1	n.938-43A>G		intron_variant	Intron 10 of 12			ENSP00000509336.1

Frequencies

GnomAD3 genomes AF: 0.000124 AC: 14 AN: 112807 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

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: 0.000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000381 AC: 7 AN: 183520 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000760

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: 0.0000732

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 148 AN: 1098269 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 50 AN XY: 363623

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000172 AC: 145 AN: 842150

Other (OTH) AF: 0.0000651 AC: 3 AN: 46097

GnomAD4 genome AF: 0.000124 AC: 14 AN: 112807 Hom.: 0 Cov.: 24 AF XY: 0.000114 AC XY: 4 AN XY: 34943

African (AFR) AF: 0.000129 AC: 4 AN: 31056

American (AMR) AF: 0.00 AC: 0 AN: 10724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6186

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

European-Non Finnish (NFE) AF: 0.000187 AC: 10 AN: 53353

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1009A>G (p.N337D) alteration is located in exon 11 (coding exon 11) of the ZRSR2 gene. This alteration results from a A to G substitution at nucleotide position 1009, causing the asparagine (N) at amino acid position 337 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.33	T
Polyphen		0.60	P
Vest4		0.70
MVP		0.57
MPC		0.69
ClinPred		0.24	T
GERP RS		5.5
Varity_R		0.67
gMVP		0.68
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768331870; hg19: chrX-15840925;