1-10639086-G-GTCGTCGTCGTCC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001079843.3(CASZ1):c.5135_5136insGGACGACGACGA(p.Glu1708_Asp1711dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 1,048,786 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: CASZ1 NM_001079843.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASZ1	NM_001079843.3	c.5135_5136insGGACGACGACGA	p.Glu1708_Asp1711dup	inframe_insertion	21/21	ENST00000377022.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASZ1	ENST00000377022.8	c.5135_5136insGGACGACGACGA	p.Glu1708_Asp1711dup	inframe_insertion	21/21	1	NM_001079843.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000453 AC: 6 AN: 132578 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000801

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 17 AN: 91066 Hom.: 0 AF XY: 0.000210 AC XY: 11 AN XY: 52464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000908

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000769

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 56 AN: 916208 Hom.: 1 Cov.: 30 AF XY: 0.0000767 AC XY: 34 AN XY: 443496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000641

Gnomad4 OTH exome AF: 0.0000985

GnomAD4 genome AF: 0.0000453 AC: 6 AN: 132578 Hom.: 0 Cov.: 31 AF XY: 0.0000620 AC XY: 4 AN XY: 64546

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000801

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000163

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

This variant, c.5124_5135dup, results in the insertion of 4 amino acid(s) of the CASZ1 protein (p.Glu1708_Asp1711dup), but otherwise preserves the integrity of the reading frame. 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 variant has not been reported in the literature in individuals affected with CASZ1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770782033; hg19: chr1-10699143;