20-45950261-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022095.4(ZNF335):c.3445A>G(p.Ile1149Val) variant causes a missense change. The variant allele was found at a frequency of 0.000615 in 1,551,276 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (7 hom.)
• Consequence: ZNF335 NM_022095.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.06

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008857846).
• BP6: Variant 20-45950261-T-C is Benign according to our data. Variant chr20-45950261-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212650.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000394 (60/152282) while in subpopulation SAS AF= 0.00622 (30/4822). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF335	NM_022095.4	c.3445A>G	p.Ile1149Val	missense_variant	22/28	ENST00000322927.3
ZNF335	XM_047440363.1	c.3445A>G	p.Ile1149Val	missense_variant	21/27
ZNF335	XM_005260504.5	c.3442A>G	p.Ile1148Val	missense_variant	21/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF335	ENST00000322927.3	c.3445A>G	p.Ile1149Val	missense_variant	22/28	1	NM_022095.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000746 AC: 149 AN: 199814 Hom.: 0 AF XY: 0.00101 AC XY: 107 AN XY: 105642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000588

Gnomad SAS exome AF: 0.00459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000639 AC: 894 AN: 1398994 Hom.: 7 Cov.: 34 AF XY: 0.000784 AC XY: 540 AN XY: 689110

Gnomad4 AFR exome AF: 0.0000950

Gnomad4 AMR exome AF: 0.000432

Gnomad4 ASJ exome AF: 0.0000465

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00465

Gnomad4 FIN exome AF: 0.0000988

Gnomad4 NFE exome AF: 0.000416

Gnomad4 OTH exome AF: 0.000886

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000822 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 12, 2014

- -

ZNF335-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.068
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.43
MVP		0.48
MPC		0.60
ClinPred		0.054	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.18

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: rs143113106; hg19: chr20-44578900;