16-31061069-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024706.5(ZNF668):c.1859G>A(p.Ter620=) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,491,286 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (106 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (64 hom.)
• Consequence: ZNF668 NM_024706.5 stop_retained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0780

Genes affected

ZNF668 (HGNC:25821): (zinc finger protein 668) 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-31061069-C-T is Benign according to our data. Variant chr16-31061069-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 786291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.078 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF668	NM_024706.5	c.1859G>A	p.Ter620=	stop_retained_variant	3/3	ENST00000300849.5
ZNF668	NM_001172669.2	c.1928G>A	p.Ter643=	stop_retained_variant	4/4
ZNF668	NM_001172668.2	c.1859G>A	p.Ter620=	stop_retained_variant	3/3
ZNF668	NM_001172670.2	c.1859G>A	p.Ter620=	stop_retained_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF668	ENST00000300849.5	c.1859G>A	p.Ter620=	stop_retained_variant	3/3	1	NM_024706.5	P1
	ENST00000622229.1	n.1646C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3081 AN: 152114 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00610 AC: 977 AN: 160118 Hom.: 33 AF XY: 0.00462 AC XY: 395 AN XY: 85564

Gnomad AFR exome AF: 0.0694

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000782

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00186 AC: 2492 AN: 1339054 Hom.: 64 Cov.: 29 AF XY: 0.00164 AC XY: 1075 AN XY: 654674

Gnomad4 AFR exome AF: 0.0685

Gnomad4 AMR exome AF: 0.00352

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00387

GnomAD4 genome AF: 0.0203 AC: 3089 AN: 152232 Hom.: 106 Cov.: 32 AF XY: 0.0195 AC XY: 1452 AN XY: 74428

Gnomad4 AFR AF: 0.0702

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0178 Hom.: 23

Bravo AF: 0.0227

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

ZNF668-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	13
Dann	Benign	0.56

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: rs74720434; hg19: chr16-31072390;