20-18384491-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367614.1(DZANK1):c.2242G>T(p.Asp748Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

Genes affected

DZANK1 (HGNC:15858): (double zinc ribbon and ankyrin repeat domains 1) This gene contains two ankyrin repeat-encoding regions. Ankyrin repeats are tandemly repeated modules of about 33 amino acids described as L-shaped structures consisting of a beta-hairpin and two alpha-helices. Ankyrin repeats occur in a large number of functionally diverse proteins, mainly from eukaryotes, and are known to function as protein-protein interaction domains. [provided by RefSeq, Dec 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30024153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DZANK1	NM_001367614.1	c.2242G>T	p.Asp748Tyr	missense_variant	21/21	ENST00000699568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DZANK1	ENST00000699568.1	c.2242G>T	p.Asp748Tyr	missense_variant	21/21		NM_001367614.1	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459788 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725920

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2023

The c.2167G>T (p.D723Y) alteration is located in exon 21 (coding exon 20) of the DZANK1 gene. This alteration results from a G to T substitution at nucleotide position 2167, causing the aspartic acid (D) at amino acid position 723 to be replaced by a tyrosine (Y). 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	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T;T;.;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	0.57	D;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.5	D;.;.;.
REVEL	Benign	0.16
Sift	Uncertain	0.010	D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.91	P;.;P;.
Vest4		0.26
MutPred		0.54		Loss of disorder (P = 0.1335);.;Loss of disorder (P = 0.1335);.;
MVP		0.35
MPC		0.14
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.24
gMVP		0.39

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: rs752231081; hg19: chr20-18365135;