20-18414379-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367614.1(DZANK1):c.1268T>C(p.Leu423Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L423V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.225

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11169669).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DZANK1	NM_001367614.1	c.1268T>C	p.Leu423Pro	missense_variant	12/21	ENST00000699568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DZANK1	ENST00000699568.1	c.1268T>C	p.Leu423Pro	missense_variant	12/21		NM_001367614.1	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Oct 03, 2023

The c.1211T>C (p.L404P) alteration is located in exon 12 (coding exon 11) of the DZANK1 gene. This alteration results from a T to C substitution at nucleotide position 1211, causing the leucine (L) at amino acid position 404 to be replaced by a proline (P). 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	0.062
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	1.3
Dann	Benign	0.72
DEOGEN2	Benign	0.0058	T;T;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.47	T;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N;.;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.13	T;.;.;.
Sift4G	Benign	0.081	T;T;T;T
Polyphen		0.044	B;.;B;.
Vest4		0.094
MutPred		0.37		Gain of disorder (P = 0.0218);.;Gain of disorder (P = 0.0218);.;
MVP		0.21
MPC		0.058
ClinPred		0.059	T
GERP RS		-3.7
Varity_R		0.14
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-18395023;