5-77077214-C-T

Variant names:

• chr5-77077214-C-T
• rs868441142
• NM_032367.4:c.665G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032367.4(ZBED3):​c.665G>A​(p.Gly222Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000267 in 1,500,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ZBED3 NM_032367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.608
• Publications: 0 publications found

Genes affected

ZBED3 (HGNC:20711): (zinc finger BED-type containing 3) This gene belongs to a class of genes that arose through hAT DNA transposition and that encode regulatory proteins. This gene is upregulated in lung cancer tissues, where the encoded protein causes an accumulation of beta-catenin and enhanced lung cancer cell invasion. In addition, the encoded protein can be secreted and be involved in resistance to insulin. [provided by RefSeq, Jul 2016]

ENSG00000285000 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04240635).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032367.4. 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
	ZBED3	NM_032367.4	MANE Select	c.665G>A	p.Gly222Asp	missense	Exon 3 of 3	NP_115743.1	Q96IU2
	ZBED3	NM_001329564.2		c.665G>A	p.Gly222Asp	missense	Exon 2 of 2	NP_001316493.1	Q96IU2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBED3	ENST00000255198.3	TSL:1 MANE Select	c.665G>A	p.Gly222Asp	missense	Exon 3 of 3	ENSP00000255198.2	Q96IU2
	ENSG00000285000	ENST00000646704.1		n.1809+15412C>T		intron	N/A	ENSP00000495089.1	A0A2R8YFF1
	ZBED3	ENST00000896398.1		c.665G>A	p.Gly222Asp	missense	Exon 4 of 4	ENSP00000566457.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1348480 Hom.: 0 Cov.: 30 AF XY: 0.00000299 AC XY: 2 AN XY: 668350

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000352 AC: 1 AN: 28406

American (AMR) AF: 0.00 AC: 0 AN: 31758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23506

East Asian (EAS) AF: 0.0000325 AC: 1 AN: 30774

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062862

Other (OTH) AF: 0.00 AC: 0 AN: 55662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.61
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.048
Sift	Benign	0.53	T
Sift4G	Benign	0.83	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.44		Loss of loop (P = 0.0203)
MVP		0.014
MPC		2.5
ClinPred		0.098	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.0057
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs868441142; hg19: chr5-76373039;