3-138062820-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Moderate BS1_Supporting

The NM_173543.3(DZIP1L):c.2300G>A(p.Trp767Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,906 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: DZIP1L NM_173543.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.55

Genes affected

DZIP1L (HGNC:26551): (DAZ interacting zinc finger protein 1 like) Predicted to enable metal ion binding activity. Involved in cilium assembly and regulation of protein localization. Located in ciliary basal body. Colocalizes with centriole. Implicated in polycystic kidney disease 5. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00174 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000269 (41/152328) while in subpopulation NFE AF= 0.000456 (31/68040). AF 95% confidence interval is 0.000329. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DZIP1L	NM_173543.3	c.2300G>A	p.Trp767Ter	stop_gained	16/16	ENST00000327532.7
DZIP1L	XM_005247198.4	c.2384G>A	p.Trp795Ter	stop_gained	16/16
DZIP1L	XM_047447642.1	c.2243G>A	p.Trp748Ter	stop_gained	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DZIP1L	ENST00000327532.7	c.2300G>A	p.Trp767Ter	stop_gained	16/16	1	NM_173543.3	P2

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251170 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135736

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: 0.00

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461578 Hom.: 2 Cov.: 31 AF XY: 0.000254 AC XY: 185 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74492

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000763

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2022	Nonsense variant predicted to result in protein truncation as the last 1 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 22, 2022	This sequence change creates a premature translational stop signal (p.Trp767*) in the DZIP1L gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the DZIP1L protein. This variant is present in population databases (rs200902457, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with DZIP1L-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	0.99	N
Vest4		0.097
GERP RS		4.6

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: rs200902457; hg19: chr3-137781662;