20-18415445-A-G

Position:

• chr20-18415445-A-G

Variant summary

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

The NM_001367614.1(DZANK1):​c.1016T>C​(p.Met339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,361,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000029 (0 hom.)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.175

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]

DZANK1 (HGNC:):

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=0.06461641).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DZANK1	NM_001367614.1	c.1016T>C	p.Met339Thr	missense_variant	11/21	ENST00000699568.1	NP_001354543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DZANK1	ENST00000699568.1	c.1016T>C	p.Met339Thr	missense_variant	11/21		NM_001367614.1	ENSP00000514442.1
DZANK1	ENST00000699590.1	c.974T>C	p.Met325Thr	missense_variant	11/21			ENSP00000514461.1
DZANK1	ENST00000699525.1	c.959T>C	p.Met320Thr	missense_variant	11/21			ENSP00000514418.1
DZANK1	ENST00000357236.8	c.362T>C	p.Met121Thr	missense_variant	7/17	5		ENSP00000349774.5
DZANK1	ENST00000377630.9	n.*147T>C		non_coding_transcript_exon_variant	10/20	2		ENSP00000366857.6
DZANK1	ENST00000460891.5	n.*1404T>C		non_coding_transcript_exon_variant	11/14	2		ENSP00000477872.1
DZANK1	ENST00000377630.9	n.*147T>C		3_prime_UTR_variant	10/20	2		ENSP00000366857.6
DZANK1	ENST00000460891.5	n.*1404T>C		3_prime_UTR_variant	11/14	2		ENSP00000477872.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1361602 Hom.: 0 Cov.: 31 AF XY: 0.00000445 AC XY: 3 AN XY: 674534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000288

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000189

Gnomad4 OTH exome AF: 0.0000180

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 14, 2023

The c.959T>C (p.M320T) alteration is located in exon 11 (coding exon 10) of the DZANK1 gene. This alteration results from a T to C substitution at nucleotide position 959, causing the methionine (M) at amino acid position 320 to be replaced by a threonine (T). 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	0.085
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.49
DANN	Benign	0.52
DEOGEN2	Benign	0.0019	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.46	T;T;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;.;.
REVEL	Benign	0.22
Sift	Benign	0.058	T;.;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.14
MutPred		0.11		Gain of glycosylation at M320 (P = 0.0052);.;Gain of glycosylation at M320 (P = 0.0052);
MVP		0.17
MPC		0.045
ClinPred		0.033	T
GERP RS		-0.23
Varity_R		0.12
gMVP		0.15

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: rs1175744808; hg19: chr20-18396089;