3-138062881-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173543.3(DZIP1L):c.2239A>G(p.Lys747Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DZIP1L NM_173543.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.944

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06597248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DZIP1L	NM_173543.3	c.2239A>G	p.Lys747Glu	missense_variant	16/16	ENST00000327532.7
DZIP1L	XM_005247198.4	c.2323A>G	p.Lys775Glu	missense_variant	16/16
DZIP1L	XM_047447642.1	c.2182A>G	p.Lys728Glu	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DZIP1L	ENST00000327532.7	c.2239A>G	p.Lys747Glu	missense_variant	16/16	1	NM_173543.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.2239A>G (p.K747E) alteration is located in exon 16 (coding exon 15) of the DZIP1L gene. This alteration results from a A to G substitution at nucleotide position 2239, causing the lysine (K) at amino acid position 747 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.029
Sift	Uncertain	0.029	D
Sift4G	Benign	0.29	T
Polyphen		0.24	B
Vest4		0.083
MVP		0.030
MPC		0.25
ClinPred		0.12	T
GERP RS		2.3
Varity_R		0.066
gMVP		0.071

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: rs1191943533; hg19: chr3-137781723;