chr20-18414398-A-T

Position:

• chr20-18414398-A-T

Variant summary

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

The NM_001367614.1(DZANK1):​c.1249T>A​(p.Leu417Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,188 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.277

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=0.051617086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DZANK1	NM_001367614.1	c.1249T>A	p.Leu417Met	missense_variant	12/21	ENST00000699568.1	NP_001354543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DZANK1	ENST00000699568.1	c.1249T>A	p.Leu417Met	missense_variant	12/21		NM_001367614.1	ENSP00000514442.1
DZANK1	ENST00000699590.1	c.1207T>A	p.Leu403Met	missense_variant	12/21			ENSP00000514461.1
DZANK1	ENST00000699525.1	c.1192T>A	p.Leu398Met	missense_variant	12/21			ENSP00000514418.1
DZANK1	ENST00000357236.8	c.595T>A	p.Leu199Met	missense_variant	8/17	5		ENSP00000349774.5
DZANK1	ENST00000377630.9	n.*380T>A		non_coding_transcript_exon_variant	11/20	2		ENSP00000366857.6
DZANK1	ENST00000460891.5	n.*1637T>A		non_coding_transcript_exon_variant	12/14	2		ENSP00000477872.1
DZANK1	ENST00000377630.9	n.*380T>A		3_prime_UTR_variant	11/20	2		ENSP00000366857.6
DZANK1	ENST00000460891.5	n.*1637T>A		3_prime_UTR_variant	12/14	2		ENSP00000477872.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.041
DANN	Benign	0.66
DEOGEN2	Benign	0.0020	T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.39	T;T;.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;L;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.25	N;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.32	T;D;.;.
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.10	B;.;B;.
Vest4		0.064
MutPred		0.21		Gain of catalytic residue at V394 (P = 0.0184);.;Gain of catalytic residue at V394 (P = 0.0184);.;
MVP		0.17
MPC		0.041
ClinPred		0.084	T
GERP RS		-5.7
Varity_R		0.061
gMVP		0.16

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: rs1293006371; hg19: chr20-18395042;