chr20-45952664-GTCAC-G

Position:

• chr20-45952664-GTCAC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_022095.4(ZNF335):​c.2744_2747delGTGA​(p.Ser915fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000131 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ZNF335 NM_022095.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.41

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-45952664-GTCAC-G is Pathogenic according to our data. Variant chr20-45952664-GTCAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45952664-GTCAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF335	NM_022095.4	c.2744_2747delGTGA	p.Ser915fs	frameshift_variant	19/28	ENST00000322927.3	NP_071378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF335	ENST00000322927.3	c.2744_2747delGTGA	p.Ser915fs	frameshift_variant	19/28	1	NM_022095.4	ENSP00000325326.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 248128 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134330

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461564 Hom.: 0 AF XY: 0.000136 AC XY: 99 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74450

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000155

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic primordial dwarfism due to ZNF335 deficiency Pathogenic:5

Likely pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2020	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant was identified as compound heterozygous in an individual with developmental delay, intellectual disability, seizures, hypomyelination, and failure to thrive. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found twice in our laboratory: in trans with an inframe deletion (V242del) in a 3-year-old female with idiopathic pulmonary arterial hypertension, significant delays, hypotonia, microcephaly, dysmorphisms, broad thumbs and halluxes, hirsutism. A similarly affected microcephalic sister was also compound heterozygous. Also found in trans with a nonsense variant (E1263X) in an 8-year-old male with microcephaly, intellectual disability, seizures, hypomyelination, partial cytochrome c oxidase deficiency. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Reported in a patient with developmental delay, seizures, hypomyelination, and failure to thrive who harbored a second pathogenic ZNF335 variant, however, segregation information was not provided (Eldomery et al., 2017); This variant is associated with the following publications: (PMID: 31216405, 31589614, 25326635, 34426522, 28327206) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jul 06, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753460205; hg19: chr20-44581303;