20-57613163-C-T

Position:

• chr20-57613163-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030776.3(ZBP1):​c.670G>A​(p.Gly224Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0087 in 1,614,172 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (88 hom.)
• Consequence: ZBP1 NM_030776.3 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.353

Genes affected

ZBP1 (HGNC:16176): (Z-DNA binding protein 1) This gene encodes a Z-DNA binding protein. The encoded protein plays a role in the innate immune response by binding to foreign DNA and inducing type-I interferon production. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006138891).
• BP6: Variant 20-57613163-C-T is Benign according to our data. Variant chr20-57613163-C-T is described in ClinVar as [Benign]. Clinvar id is 770672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00885 (12944/1461872) while in subpopulation MID AF= 0.0369 (213/5768). AF 95% confidence interval is 0.0329. There are 88 homozygotes in gnomad4_exome. There are 6807 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBP1	NM_030776.3	c.670G>A	p.Gly224Ser	missense_variant, splice_region_variant	5/8	ENST00000371173.8	NP_110403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBP1	ENST00000371173.8	c.670G>A	p.Gly224Ser	missense_variant, splice_region_variant	5/8	1	NM_030776.3	ENSP00000360215	P2

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1099 AN: 152182 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00954

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00828 AC: 2081 AN: 251380 Hom.: 22 AF XY: 0.00930 AC XY: 1264 AN XY: 135874

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00912

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00885 AC: 12944 AN: 1461872 Hom.: 88 Cov.: 31 AF XY: 0.00936 AC XY: 6807 AN XY: 727236

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.000992

Gnomad4 NFE exome AF: 0.00885

Gnomad4 OTH exome AF: 0.00995

GnomAD4 genome AF: 0.00720 AC: 1096 AN: 152300 Hom.: 6 Cov.: 33 AF XY: 0.00720 AC XY: 536 AN XY: 74460

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00954

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00932 Hom.: 15

Bravo AF: 0.00762

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00867 AC: 1052

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.042	T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.46	T;T;T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.086
Sift	Benign	0.050	D;D;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.15
MVP		0.095
MPC		0.049
ClinPred		0.034	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41304401; hg19: chr20-56188219; COSMIC: COSV59062231; COSMIC: COSV59062231;