20-45967636-TG-T

Variant names:

• chr20-45967636-TG-T
• rs551678383
• NM_022095.4:c.815-3delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022095.4(ZNF335):​c.815-3delC variant causes a splice region, 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.127
• Publications: 2 publications found

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]

ZNF335 Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism due to ZNF335 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022095.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	NM_022095.4	MANE Select	c.815-3delC		splice_region intron	N/A	NP_071378.1	Q9H4Z2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	ENST00000322927.3	TSL:1 MANE Select	c.815-3delC		splice_region intron	N/A	ENSP00000325326.2	Q9H4Z2-1
	ZNF335	ENST00000944756.1		c.815-3delC		splice_region intron	N/A	ENSP00000614815.1
	ZNF335	ENST00000862676.1		c.815-6delC		splice_region intron	N/A	ENSP00000532735.1

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

GnomAD2 exomes AF: 0.00684 AC: 1717 AN: 251104 AF XY: 0.00664

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 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

African (AFR) AF: 0.00188 AC: 63 AN: 33478

American (AMR) AF: 0.00365 AC: 163 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 325 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86250

European-Finnish (FIN) AF: 0.00475 AC: 253 AN: 53256

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15086 AN: 1111952

Other (OTH) AF: 0.00904 AC: 546 AN: 60388

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

African (AFR) AF: 0.00212 AC: 88 AN: 41562

American (AMR) AF: 0.00438 AC: 67 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00887 Hom.: 2

Bravo AF: 0.00691

EpiCase AF: 0.0122

EpiControl AF: 0.00978

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Microcephalic primordial dwarfism due to ZNF335 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs551678383; hg19: chr20-44596275;