rs150750750

Positions:

• chr20-45949256-AGG-A

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.3820-7_3820-6del 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 0.000597 in 1,613,774 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: ZNF335 NM_022095.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.506

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 20-45949256-AGG-A is Benign according to our data. Variant chr20-45949256-AGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 437354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00303 (461/152202) while in subpopulation AFR AF= 0.0102 (422/41524). AF 95% confidence interval is 0.00936. There are 1 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF335	NM_022095.4	c.3820-7_3820-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000322927.3
ZNF335	XM_005260504.5	c.3817-7_3817-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ZNF335	XM_047440363.1	c.3820-7_3820-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF335	ENST00000322927.3	c.3820-7_3820-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_022095.4	P1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152084 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000849 AC: 213 AN: 250912 Hom.: 1 AF XY: 0.000707 AC XY: 96 AN XY: 135744

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000343 AC: 502 AN: 1461572 Hom.: 2 AF XY: 0.000300 AC XY: 218 AN XY: 727090

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152202 Hom.: 1 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74420

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00350

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 23, 2015

- -

Microcephalic primordial dwarfism due to ZNF335 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150750750; hg19: chr20-44577895;