1-10639009-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079843.3(CASZ1):c.5213C>G(p.Pro1738Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 991,076 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (609 hom., cov: 32)
  • Exomes 𝑓: 0.042 (969 hom.)
• Consequence: CASZ1 NM_001079843.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182

Genes affected

CASZ1 (HGNC:26002): (castor zinc finger 1) The protein encoded by this gene is a zinc finger transcription factor. The encoded protein may function as a tumor suppressor, and single nucleotide polymorphisms in this gene are associated with blood pressure variation. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011253357).
• BP6: Variant 1-10639009-G-C is Benign according to our data. Variant chr1-10639009-G-C is described in ClinVar as [Benign]. Clinvar id is 1294667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASZ1	NM_001079843.3	c.5213C>G	p.Pro1738Arg	missense_variant	21/21	ENST00000377022.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASZ1	ENST00000377022.8	c.5213C>G	p.Pro1738Arg	missense_variant	21/21	1	NM_001079843.3	P1

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10168 AN: 145726 Hom.: 606 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0724

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0600

GnomAD3 exomes AF: 0.0573 AC: 295 AN: 5146 Hom.: 23 AF XY: 0.0675 AC XY: 210 AN XY: 3112

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.0833

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0423 AC: 35775 AN: 845302 Hom.: 969 Cov.: 32 AF XY: 0.0425 AC XY: 16669 AN XY: 392174

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.0645

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0321

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0698 AC: 10173 AN: 145774 Hom.: 609 Cov.: 32 AF XY: 0.0681 AC XY: 4827 AN XY: 70912

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0386

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.0345

Gnomad4 OTH AF: 0.0595

Alfa AF: 0.0503 Hom.: 43

ExAC AF: 0.0174 AC: 403

Asia WGS AF: 0.0420 AC: 85 AN: 2046

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.89	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.041
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.055	T
Polyphen		0.018	B
Vest4		0.034
ClinPred		0.034	T
GERP RS		2.0
Varity_R		0.094
gMVP		0.054

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: rs184511437; hg19: chr1-10699066; COSMIC: COSV100984848; COSMIC: COSV100984848;