rs141812371

chr20-45950050-G-Achr20-45950050-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022095.4(ZNF335):c.3507C>T(p.His1169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,613,904 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: ZNF335 NM_022095.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0480

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-45950050-G-A is Benign according to our data. Variant chr20-45950050-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.048 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00384 (585/152330) while in subpopulation AFR AF= 0.0127 (526/41566). AF 95% confidence interval is 0.0118. There are 5 homozygotes in gnomad4. There are 288 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF335	NM_022095.4	c.3507C>T	p.His1169=	synonymous_variant	23/28	ENST00000322927.3
ZNF335	XM_047440363.1	c.3507C>T	p.His1169=	synonymous_variant	22/27
ZNF335	XM_005260504.5	c.3504C>T	p.His1168=	synonymous_variant	22/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF335	ENST00000322927.3	c.3507C>T	p.His1169=	synonymous_variant	23/28	1	NM_022095.4	P1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 152212 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00104 AC: 260 AN: 249738 Hom.: 0 AF XY: 0.000881 AC XY: 119 AN XY: 135124

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461574 Hom.: 2 Cov.: 33 AF XY: 0.000363 AC XY: 264 AN XY: 727086

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152330 Hom.: 5 Cov.: 33 AF XY: 0.00387 AC XY: 288 AN XY: 74490

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00456

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 17, 2018

- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.053
Dann	Benign	0.69

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: rs141812371; hg19: chr20-44578689;