rs551678383

chr20-45967636-TG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022095.4(ZNF335):c.815-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,914 control chromosomes in the GnomAD database, including 119 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (3 hom., cov: 32)
  • Exomes 𝑓: 0.011 (116 hom.)
• Consequence: ZNF335 NM_022095.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.127

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 -16 ACMG points.

• BP6: Variant 20-45967636-TG-T is Benign according to our data. Variant chr20-45967636-TG-T is described in ClinVar as [Benign]. Clinvar id is 130808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00687 (1046/152280) while in subpopulation NFE AF= 0.0116 (789/68018). AF 95% confidence interval is 0.0109. There are 3 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF335	NM_022095.4	c.815-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000322927.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF335	ENST00000322927.3	c.815-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_022095.4	P1
ZNF335	ENST00000476822.1	n.1148-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
ZNF335	ENST00000494955.1	n.1126-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1046 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00684 AC: 1717 AN: 251104 Hom.: 9 AF XY: 0.00664 AC XY: 902 AN XY: 135790

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00389

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.0113 AC: 16555 AN: 1461634 Hom.: 116 Cov.: 73 AF XY: 0.0108 AC XY: 7866 AN XY: 727142

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00904

GnomAD4 genome AF: 0.00687 AC: 1046 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74464

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00887 Hom.: 2

Bravo AF: 0.00691

EpiCase AF: 0.0122

EpiControl AF: 0.00978

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ZNF335: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 19, 2015

- -

Microcephalic primordial dwarfism due to ZNF335 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs551678383; hg19: chr20-44596275;