1-10639015-C-T

Position:

• chr1-10639015-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001079843.3(CASZ1):​c.5207G>A​(p.Arg1736Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 998,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: CASZ1 NM_001079843.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.375

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065540075).
• BS2: High AC in GnomAd4 at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASZ1	NM_001079843.3	c.5207G>A	p.Arg1736Gln	missense_variant	21/21	ENST00000377022.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASZ1	ENST00000377022.8	c.5207G>A	p.Arg1736Gln	missense_variant	21/21	1	NM_001079843.3	P1

Frequencies

GnomAD3 genomes AF: 0.000857 AC: 125 AN: 145858 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000272

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000999

GnomAD3 exomes AF: 0.0000990 AC: 1 AN: 10104 Hom.: 0 AF XY: 0.000159 AC XY: 1 AN XY: 6308

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 53 AN: 852726 Hom.: 1 Cov.: 32 AF XY: 0.0000579 AC XY: 23 AN XY: 396934

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000259

Gnomad4 OTH exome AF: 0.000143

GnomAD4 genome AF: 0.000857 AC: 125 AN: 145898 Hom.: 0 Cov.: 32 AF XY: 0.000803 AC XY: 57 AN XY: 70968

Gnomad4 AFR AF: 0.00292

Gnomad4 AMR AF: 0.000272

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000991

Alfa AF: 0.000712 Hom.: 0

ExAC AF: 0.000109 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.5207G>A (p.R1736Q) alteration is located in exon 21 (coding exon 18) of the CASZ1 gene. This alteration results from a G to A substitution at nucleotide position 5207, causing the arginine (R) at amino acid position 1736 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CASZ1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1736 of the CASZ1 protein (p.Arg1736Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.97	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.032
Sift	Uncertain	0.016	D
Sift4G	Benign	0.20	T
Polyphen		0.031	B
Vest4		0.14
MVP		0.043
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.046

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: rs750374432; hg19: chr1-10699072;