X-15823063-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005089.4(ZRSR2):c.1270G>C(p.Gly424Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16564092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZRSR2	NM_005089.4	c.1270G>C	p.Gly424Arg	missense_variant	11/11	ENST00000307771.8
ZRSR2	XM_011545589.4	c.1339G>C	p.Gly447Arg	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZRSR2	ENST00000307771.8	c.1270G>C	p.Gly424Arg	missense_variant	11/11	1	NM_005089.4	P2
ZRSR2	ENST00000684799.1	c.1192G>C	p.Gly398Arg	missense_variant	10/11			A2
ZRSR2	ENST00000690252.1	c.1270G>C	p.Gly424Arg	missense_variant, NMD_transcript_variant	11/13
ZRSR2	ENST00000691502.1	c.1156G>C	p.Gly386Arg	missense_variant, NMD_transcript_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.1270G>C (p.G424R) alteration is located in exon 11 (coding exon 11) of the ZRSR2 gene. This alteration results from a G to C substitution at nucleotide position 1270, causing the glycine (G) at amino acid position 424 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0099	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.82	T
Polyphen		0.012	B
Vest4		0.19
MutPred		0.25		Loss of loop (P = 0.0512);
MVP		0.12
MPC		0.49
ClinPred		0.58	D
GERP RS		3.9
Varity_R		0.099
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15841186;