5-77077658-T-A

Variant names:

• chr5-77077658-T-A
• rs1345944526
• NM_032367.4:c.221A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032367.4(ZBED3):​c.221A>T​(p.Glu74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E74Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: ZBED3 NM_032367.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3215923).

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.221A>T	p.Glu74Val	missense	Exon 3 of 3	NP_115743.1	Q96IU2
	ZBED3	NM_001329564.2		c.221A>T	p.Glu74Val	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.221A>T	p.Glu74Val	missense	Exon 3 of 3	ENSP00000255198.2	Q96IU2
	ENSG00000285000	ENST00000646704.1		n.1809+15856T>A		intron	N/A	ENSP00000495089.1	A0A2R8YFF1
	ZBED3	ENST00000896398.1		c.221A>T	p.Glu74Val	missense	Exon 4 of 4	ENSP00000566457.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151390 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: 0.000196

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 AF: 7.98e-7 AC: 1 AN: 1253712 Hom.: 0 Cov.: 31 AF XY: 0.00000162 AC XY: 1 AN XY: 616650

African (AFR) AF: 0.00 AC: 0 AN: 25398

American (AMR) AF: 0.00 AC: 0 AN: 20178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20720

East Asian (EAS) AF: 0.00 AC: 0 AN: 27094

South Asian (SAS) AF: 0.00 AC: 0 AN: 62158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3596

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013084

Other (OTH) AF: 0.00 AC: 0 AN: 51172

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151390 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73922

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

African (AFR) AF: 0.00 AC: 0 AN: 41296

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67804

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.0023
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.56
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.089
Sift	Benign	0.079	T
Sift4G	Benign	0.087	T
Polyphen		0.97	D
Vest4		0.28
MutPred		0.51		Gain of sheet (P = 0.0221)
MVP		0.37
MPC		2.6
ClinPred		0.75	D
GERP RS		3.5
Varity_R		0.15
gMVP		0.23
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1345944526; hg19: chr5-76373483;