19-53407838-C-A

Variant summary

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

The NM_001040185.3(ZNF765):c.283C>A(p.His95Asn) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF765 NM_001040185.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.95

Genes affected

ZNF765 (HGNC:25092): (zinc finger protein 765) 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]

ZNF765-ZNF761 (HGNC:):

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=0.11141205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF765	NM_001040185.3	c.283C>A	p.His95Asn	missense_variant	4/4	ENST00000396408.8
ZNF765-ZNF761	NM_001350496.2	c.-1345+5647C>A		intron_variant
ZNF765	NM_001350495.2	c.124C>A	p.His42Asn	missense_variant	3/3
ZNF765	NR_146721.2	n.260+5647C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF765	ENST00000396408.8	c.283C>A	p.His95Asn	missense_variant	4/4	1	NM_001040185.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249602 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135238

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Sep 27, 2022

The c.283C>A (p.H95N) alteration is located in exon 4 (coding exon 3) of the ZNF765 gene. This alteration results from a C to A substitution at nucleotide position 283, causing the histidine (H) at amino acid position 95 to be replaced by an asparagine (N). 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	0.079
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	2.6
Dann	Benign	0.71
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Benign	0.084
Sift	Benign	0.063	T;D
Sift4G	Benign	0.12	T;D
Polyphen		0.092	B;.
Vest4		0.12
MutPred		0.22		Loss of ubiquitination at K92 (P = 0.1498);.;
MVP		0.13
MPC		0.051
ClinPred		0.20	T
GERP RS		0.072
Varity_R		0.14
gMVP		0.013

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: rs746730483; hg19: chr19-53911091;