rs41309565

Variant names:

• chrX-15809200-T-C
• rs41309565
• NM_005089.4:c.439T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005089.4(ZRSR2):​c.439T>C​(p.Leu147Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,193,471 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000038 (0 hom. 14 hem.)
• Consequence: ZRSR2 NM_005089.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007138
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-15809200-T-C is Benign according to our data. Variant chrX-15809200-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3199288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.013 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRSR2	NM_005089.4	c.439T>C	p.Leu147Leu	splice_region_variant, synonymous_variant	Exon 7 of 11	ENST00000307771.8	NP_005080.1
ZRSR2	XM_011545589.4	c.508T>C	p.Leu170Leu	splice_region_variant, synonymous_variant	Exon 6 of 10		XP_011543891.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRSR2	ENST00000307771.8	c.439T>C	p.Leu147Leu	splice_region_variant, synonymous_variant	Exon 7 of 11	1	NM_005089.4	ENSP00000303015.7
ZRSR2	ENST00000684799.1	c.361T>C	p.Leu121Leu	splice_region_variant, synonymous_variant	Exon 6 of 11			ENSP00000510773.1
ZRSR2	ENST00000690252.1	n.439T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 13			ENSP00000510140.1
ZRSR2	ENST00000691502.1	n.439T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 13			ENSP00000509336.1

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112509 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000552

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000768 AC: 14 AN: 182279 AF XY: 0.0000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000798

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000379 AC: 41 AN: 1080909 Hom.: 0 Cov.: 27 AF XY: 0.0000401 AC XY: 14 AN XY: 348779

African (AFR) AF: 0.00 AC: 0 AN: 26068

American (AMR) AF: 0.00 AC: 0 AN: 35117

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.000299 AC: 9 AN: 30126

South Asian (SAS) AF: 0.00 AC: 0 AN: 53579

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.0000351 AC: 29 AN: 826608

Other (OTH) AF: 0.0000659 AC: 3 AN: 45525

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112562 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34732

African (AFR) AF: 0.00 AC: 0 AN: 31039

American (AMR) AF: 0.00 AC: 0 AN: 10626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.000554 AC: 2 AN: 3611

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6179

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53286

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 21, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.5
DANN	Benign	0.69
PhyloP100		0.013
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.048
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

Other links and lift over

dbSNP: rs41309565; hg19: chrX-15827323;