X-15815867-G-C

Variant names:

• chrX-15815867-G-C
• rs587778767
• NM_005089.4:c.748G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005089.4(ZRSR2):​c.748G>C​(p.Val250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,094,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V250M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.54
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3147387).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZRSR2	NM_005089.4	MANE Select	c.748G>C	p.Val250Leu	missense	Exon 8 of 11	NP_005080.1	Q15696

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZRSR2	ENST00000307771.8	TSL:1 MANE Select	c.748G>C	p.Val250Leu	missense	Exon 8 of 11	ENSP00000303015.7	Q15696
	ZRSR2	ENST00000964213.1		c.766G>C	p.Val256Leu	missense	Exon 8 of 11	ENSP00000634272.1
	ZRSR2	ENST00000964212.1		c.748G>C	p.Val250Leu	missense	Exon 8 of 11	ENSP00000634271.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094556 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 360150

African (AFR) AF: 0.00 AC: 0 AN: 26374

American (AMR) AF: 0.00 AC: 0 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19146

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30158

South Asian (SAS) AF: 0.00 AC: 0 AN: 53463

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40379

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839962

Other (OTH) AF: 0.00 AC: 0 AN: 45955

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.54	N
PhyloP100		6.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.54	T
Polyphen		0.60	P
Vest4		0.41
MutPred		0.58		Loss of methylation at K252 (P = 0.0891)
MVP		0.38
MPC		0.75
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.76
Mutation Taster		=88/12	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: rs587778767; hg19: chrX-15833990;