X-15823100-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005089.4(ZRSR2):c.1307G>C(p.Gly436Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. G436D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03195247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZRSR2	NM_005089.4	c.1307G>C	p.Gly436Ala	missense_variant	11/11	ENST00000307771.8
ZRSR2	XM_011545589.4	c.1376G>C	p.Gly459Ala	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZRSR2	ENST00000307771.8	c.1307G>C	p.Gly436Ala	missense_variant	11/11	1	NM_005089.4	P2
ZRSR2	ENST00000684799.1	c.1229G>C	p.Gly410Ala	missense_variant	10/11			A2
ZRSR2	ENST00000690252.1	c.1307G>C	p.Gly436Ala	missense_variant, NMD_transcript_variant	11/13
ZRSR2	ENST00000691502.1	c.1193G>C	p.Gly398Ala	missense_variant, NMD_transcript_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.97
Cadd	Benign	4.7
Dann	Benign	0.67
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.014
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.15
MPC		0.44
ClinPred		0.037	T
GERP RS		1.8
Varity_R		0.043
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs587778766; hg19: chrX-15841223;