19-40034611-C-T

Position:

• chr19-40034611-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005851.3(ZNF780B):​c.2248G>A​(p.Glu750Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF780B NM_001005851.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

ZNF780B (HGNC:33109): (zinc finger protein 780B) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16594234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF780B	NM_001005851.3	c.2248G>A	p.Glu750Lys	missense_variant	5/5	ENST00000434248.6	NP_001005851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF780B	ENST00000434248.6	c.2248G>A	p.Glu750Lys	missense_variant	5/5	5	NM_001005851.3	ENSP00000391641.1
ZNF780B	ENST00000221355.10	c.1804G>A	p.Glu602Lys	missense_variant	6/6	2		ENSP00000221355.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The c.2248G>A (p.E750K) alteration is located in exon 5 (coding exon 4) of the ZNF780B gene. This alteration results from a G to A substitution at nucleotide position 2248, causing the glutamic acid (E) at amino acid position 750 to be replaced by a lysine (K). 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	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.0055	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	.;N;D
REVEL	Benign	0.042
Sift	Benign	0.040	.;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.94	P;P;.
Vest4		0.15
MutPred		0.51		Gain of methylation at E750 (P = 0.0024);Gain of methylation at E750 (P = 0.0024);.;
MVP		0.43
MPC		0.33
ClinPred		0.82	D
GERP RS		2.5
Varity_R		0.13
gMVP		0.013

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-40540518;