NM_005089.4:c.1040A>G

Variant names:

• chrX-15822833-A-G
• rs762178833
• NM_005089.4:c.1040A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005089.4(ZRSR2):​c.1040A>G​(p.Tyr347Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,211,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: ZRSR2 NM_005089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33867168).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

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.1040A>G	p.Tyr347Cys	missense	Exon 11 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.1040A>G	p.Tyr347Cys	missense	Exon 11 of 11	ENSP00000303015.7	Q15696
	ZRSR2	ENST00000964213.1		c.1058A>G	p.Tyr353Cys	missense	Exon 11 of 11	ENSP00000634272.1
	ZRSR2	ENST00000964212.1		c.1052A>G	p.Tyr351Cys	missense	Exon 11 of 11	ENSP00000634271.1

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112786 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183523 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098266 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363620

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: 0.0000993 AC: 3 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: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842148

Other (OTH) AF: 0.0000217 AC: 1 AN: 46097

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112839 Hom.: 0 Cov.: 24 AF XY: 0.0000286 AC XY: 1 AN XY: 34991

African (AFR) AF: 0.00 AC: 0 AN: 31124

American (AMR) AF: 0.00 AC: 0 AN: 10750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6181

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53335

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.48		Gain of catalytic residue at L348 (P = 0.0125)
MVP		0.55
MPC		0.54
ClinPred		0.51	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.75
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs762178833; hg19: chrX-15840956;