20-57615578-C-T

Variant names:

• chr20-57615578-C-T
• rs2073145
• NM_030776.3:c.262G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030776.3(ZBP1):​c.262G>A​(p.Glu88Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,611,400 control chromosomes in the GnomAD database, including 379,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E88Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (28621 hom., cov: 31)
  • Exomes 𝑓: 0.69 (350718 hom.)
• Consequence: ZBP1 NM_030776.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• Publications: 38 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3352924E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030776.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBP1	NM_030776.3	MANE Select	c.262G>A	p.Glu88Lys	missense splice_region	Exon 3 of 8	NP_110403.2	Q9H171-1
	ZBP1	NM_001160417.2		c.262G>A	p.Glu88Lys	missense splice_region	Exon 3 of 8	NP_001153889.1
	ZBP1	NM_001160418.2		c.37G>A	p.Glu13Lys	missense splice_region	Exon 2 of 7	NP_001153890.1	Q9H171-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBP1	ENST00000371173.8	TSL:1 MANE Select	c.262G>A	p.Glu88Lys	missense splice_region	Exon 3 of 8	ENSP00000360215.3	Q9H171-1
	ZBP1	ENST00000395822.7	TSL:2	c.37G>A	p.Glu13Lys	missense splice_region	Exon 2 of 7	ENSP00000379167.3	Q9H171-7
	ZBP1	ENST00000857154.1		c.37G>A	p.Glu13Lys	missense splice_region	Exon 2 of 7	ENSP00000527213.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89188 AN: 151718 Hom.: 28612 Cov.: 31

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.691 AC: 172458 AN: 249400 AF XY: 0.703

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.754

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.737

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.690

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.689 AC: 1005490 AN: 1459566 Hom.: 350718 Cov.: 47 AF XY: 0.694 AC XY: 503823 AN XY: 726176

African (AFR) AF: 0.293 AC: 9763 AN: 33320

American (AMR) AF: 0.747 AC: 33080 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 15922 AN: 26020

East Asian (EAS) AF: 0.707 AC: 27981 AN: 39576

South Asian (SAS) AF: 0.836 AC: 71933 AN: 86052

European-Finnish (FIN) AF: 0.690 AC: 36830 AN: 53390

Middle Eastern (MID) AF: 0.731 AC: 4198 AN: 5744

European-Non Finnish (NFE) AF: 0.689 AC: 765309 AN: 1110890

Other (OTH) AF: 0.672 AC: 40474 AN: 60270

GnomAD4 genome AF: 0.588 AC: 89218 AN: 151834 Hom.: 28621 Cov.: 31 AF XY: 0.596 AC XY: 44186 AN XY: 74194

African (AFR) AF: 0.304 AC: 12568 AN: 41322

American (AMR) AF: 0.684 AC: 10460 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2128 AN: 3470

East Asian (EAS) AF: 0.729 AC: 3740 AN: 5132

South Asian (SAS) AF: 0.838 AC: 4037 AN: 4820

European-Finnish (FIN) AF: 0.694 AC: 7331 AN: 10558

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46850 AN: 67934

Other (OTH) AF: 0.606 AC: 1277 AN: 2106

Alfa AF: 0.649 Hom.: 98540

Bravo AF: 0.571

TwinsUK AF: 0.689 AC: 2554

ALSPAC AF: 0.687 AC: 2649

ESP6500AA AF: 0.312 AC: 1373

ESP6500EA AF: 0.684 AC: 5886

ExAC AF: 0.686 AC: 83251

Asia WGS AF: 0.732 AC: 2547 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.73
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	9.3e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.060	N
PhyloP100		-0.39
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.10	T
Sift4G	Benign	0.31	T
Polyphen		0.0060	B
Vest4		0.021
MPC		0.049
ClinPred		0.0068	T
GERP RS		-1.1
Varity_R		0.028
gMVP		0.44
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2073145; hg19: chr20-56190634; COSMIC: COSV107408402;