rs117132825

chr20-45960265-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022095.4(ZNF335):c.1963C>T(p.Pro655Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,152 control chromosomes in the GnomAD database, including 259 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0076 (16 hom., cov: 32)
  • Exomes 𝑓: 0.012 (243 hom.)
• Consequence: ZNF335 NM_022095.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.93

Genes affected

ZNF335 (HGNC:15807): (zinc finger protein 335) The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005218357).
• BP6: Variant 20-45960265-G-A is Benign according to our data. Variant chr20-45960265-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0076 (1158/152282) while in subpopulation SAS AF= 0.0447 (216/4828). AF 95% confidence interval is 0.0399. There are 16 homozygotes in gnomad4. There are 583 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF335	NM_022095.4	c.1963C>T	p.Pro655Ser	missense_variant	14/28	ENST00000322927.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF335	ENST00000322927.3	c.1963C>T	p.Pro655Ser	missense_variant	14/28	1	NM_022095.4	P1

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1161 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0117 AC: 2944 AN: 251418 Hom.: 58 AF XY: 0.0139 AC XY: 1886 AN XY: 135894

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0465

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0124 AC: 18177 AN: 1461870 Hom.: 243 Cov.: 33 AF XY: 0.0136 AC XY: 9875 AN XY: 727238

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0454

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00760 AC: 1158 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00783 AC XY: 583 AN XY: 74452

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0447

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00945 Hom.: 12

Bravo AF: 0.00622

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.0120 AC: 1452

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0109

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 27, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 24, 2014

- -

ZNF335-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

This variant is classified as 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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.84	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.47	T
Polyphen		0.92	P
Vest4		0.14
MPC		0.36
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.024
gMVP		0.44

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: rs117132825; hg19: chr20-44588904; COSMIC: COSV99071815; COSMIC: COSV99071815;