5-77077661-C-G

Variant names:

• chr5-77077661-C-G
• rs1743049441
• NM_032367.4:c.218G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032367.4(ZBED3):​c.218G>C​(p.Gly73Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G73R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZBED3 NM_032367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED3	NM_032367.4	c.218G>C	p.Gly73Ala	missense_variant	Exon 3 of 3	ENST00000255198.3	NP_115743.1
ZBED3	NM_001329564.2	c.218G>C	p.Gly73Ala	missense_variant	Exon 2 of 2		NP_001316493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBED3	ENST00000255198.3	c.218G>C	p.Gly73Ala	missense_variant	Exon 3 of 3	1	NM_032367.4	ENSP00000255198.2
ENSG00000285000	ENST00000646704.1	n.1809+15859C>G		intron_variant	Intron 13 of 15			ENSP00000495089.1
ZBED3	ENST00000511587.1	c.218G>C	p.Gly73Ala	missense_variant	Exon 2 of 2	3		ENSP00000427487.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151764 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 Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74128

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218G>C (p.G73A) alteration is located in exon 3 (coding exon 1) of the ZBED3 gene. This alteration results from a G to C substitution at nucleotide position 218, causing the glycine (G) at amino acid position 73 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.021	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.31
MutPred		0.85		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.13
MPC		2.7
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.33
gMVP		0.10

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: rs1743049441; hg19: chr5-76373486;