3-138064723-C-A

Variant names:

• chr3-138064723-C-A
• rs34517099
• NM_173543.3:c.2047G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_173543.3(DZIP1L):​c.2047G>T​(p.Glu683*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DZIP1L NM_173543.3 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.943

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.112 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DZIP1L	NM_173543.3	c.2047G>T	p.Glu683*	stop_gained	Exon 15 of 16	ENST00000327532.7	NP_775814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DZIP1L	ENST00000327532.7	c.2047G>T	p.Glu683*	stop_gained	Exon 15 of 16	1	NM_173543.3	ENSP00000332148.2
DZIP1L	ENST00000486487.1	c.154G>T	p.Glu52*	stop_gained	Exon 2 of 2	3		ENSP00000417228.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the DZIP1L gene demonstrated a sequence change, c.2047G>T, which results in the creation of a premature stop codon at amino acid position 683, p.Glu683*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated DZIP1L protein with potentially abnormal function. This sequence change has not been described in the population databases such as ExAC and gnomAD. This sequence change does not appear to have been previously described in individuals with DZIP1L-related disorders. To date no other truncating variants have been described that are distal of this variant in this gene. The functional significance of this sequence change is not known at present and its contribution to this individual’s disease phenotype cannot definitively be determined. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	0.97
Eigen	Benign	0.079
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.066	N
Vest4		0.12
ClinPred		0.68	D
GERP RS		1.1

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: rs34517099; hg19: chr3-137783565;