19-57753808-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173632.4(ZNF776):c.678C>A(p.His226Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF776 NM_173632.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35

Genes affected

ZNF776 (HGNC:26765): (zinc finger protein 776) Predicted to enable DNA-binding transcription factor 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32281274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF776	NM_173632.4	c.678C>A	p.His226Gln	missense_variant	3/3	ENST00000317178.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF776	ENST00000317178.10	c.678C>A	p.His226Gln	missense_variant	3/3	1	NM_173632.4	P1
ZNF776	ENST00000451849.1	c.108+2897C>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Feb 28, 2023

The c.678C>A (p.H226Q) alteration is located in exon 3 (coding exon 3) of the ZNF776 gene. This alteration results from a C to A substitution at nucleotide position 678, causing the histidine (H) at amino acid position 226 to be replaced by a glutamine (Q). 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	0.25
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	7.0
Dann	Uncertain	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.0040	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.37
Sift	Benign	0.12	T
Sift4G	Uncertain	0.049	D
Polyphen		0.98	D
Vest4		0.16
MutPred		0.62		Gain of disorder (P = 0.1716);
MVP		0.81
MPC		0.087
ClinPred		0.80	D
GERP RS		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.046

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-58265176;