3-75741365-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001290208.3(ZNF717):c.188A>T(p.His63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.31 (0 hom., cov: 38)
  • Exomes 𝑓: 0.15 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF717 NM_001290208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0520

Genes affected

ZNF717 (HGNC:29448): (zinc finger protein 717) This gene encodes a Kruppel-associated box (KRAB) zinc-finger protein, which belongs to a large group of transcriptional regulators in mammals. These proteins bind nucleic acids and play important roles in various cellular functions, including cell proliferation, differentiation and apoptosis, and in regulating viral replication and transcription. A pseudogene of this gene was identified on chromosome 1. [provided by RefSeq, May 2016]

LINC00960 (HGNC:48710): (long intergenic non-protein coding RNA 960)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013648868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF717	NM_001290208.3	c.188A>T	p.His63Leu	missense_variant	4/5	ENST00000652011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF717	ENST00000652011.2	c.188A>T	p.His63Leu	missense_variant	4/5		NM_001290208.3	P1
LINC00960	ENST00000668145.1	n.1243T>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 35808 AN: 115134 Hom.: 0 Cov.: 38 FAILED QC

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.337

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.0000657 AC: 3 AN: 45660 Hom.: 0 AF XY: 0.0000829 AC XY: 2 AN XY: 24134

Gnomad AFR exome AF: 0.00

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: 0.000514

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.150 AC: 120377 AN: 800452 Hom.: 0 Cov.: 27 AF XY: 0.150 AC XY: 59416 AN XY: 396538

Gnomad4 AFR exome AF: 0.0900

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.0963

Gnomad4 SAS exome AF: 0.0742

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.311 AC: 35826 AN: 115226 Hom.: 0 Cov.: 38 AF XY: 0.304 AC XY: 17112 AN XY: 56318

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.315

Alfa AF: 0.344 Hom.: 0

ExAC AF: 0.0104 AC: 101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2020

This sequence change replaces AA1 with AA2 at codon 63 of the ZNF717 protein (p.His63Leu). The AA1 residue is AA_CONSERV conserved and there is a PHYSIOCHEM_SIZE physicochemical difference between AA1 and AA2. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with ZNF717-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "SIFT_OUTPUT"; PolyPhen-2: "Benign"; Align-GVGD: "Class ALIGN_GVGD_OUTPUT. The AA2 amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	13
Dann	Benign	0.39
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.058	T;T;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-8.0	D;N;D;D
REVEL	Benign	0.19
Sift	Benign	0.15	T;T;D;T
Sift4G	Benign	0.27	T;T;.;.
Vest4		0.075
ClinPred		0.16	T
GERP RS		0.47
gMVP		0.0082

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: rs201105907; hg19: chr3-75790516; COSMIC: COSV68862982; COSMIC: COSV68862982;