rs112458662

Variant names:

• chr20-45965619-A-G
• rs112458662
• NM_022095.4:c.1102+9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022095.4(ZNF335):​c.1102+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,591,476 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (24 hom.)
• Consequence: ZNF335 NM_022095.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.635
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-45965619-A-G is Benign according to our data. Variant chr20-45965619-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446071.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 = 0.00934 (1420/152044) while in subpopulation AFR AF = 0.0327 (1357/41490). AF 95% confidence interval is 0.0313. There are 20 homozygotes in GnomAd4. There are 673 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.1102+9T>C		intron	N/A	NP_071378.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	ENST00000322927.3	TSL:1 MANE Select	c.1102+9T>C		intron	N/A	ENSP00000325326.2
	ZNF335	ENST00000944756.1		c.1102+9T>C		intron	N/A	ENSP00000614815.1
	ZNF335	ENST00000862676.1		c.1099+9T>C		intron	N/A	ENSP00000532735.1

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1415 AN: 151926 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00195 AC: 439 AN: 225478 AF XY: 0.00154

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.000976 AC: 1405 AN: 1439432 Hom.: 24 Cov.: 32 AF XY: 0.000828 AC XY: 593 AN XY: 716460

African (AFR) AF: 0.0351 AC: 1091 AN: 31088

American (AMR) AF: 0.00124 AC: 52 AN: 41824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 36864

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84928

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52376

Middle Eastern (MID) AF: 0.00243 AC: 11 AN: 4528

European-Non Finnish (NFE) AF: 0.000104 AC: 115 AN: 1103044

Other (OTH) AF: 0.00221 AC: 131 AN: 59312

GnomAD4 genome AF: 0.00934 AC: 1420 AN: 152044 Hom.: 20 Cov.: 31 AF XY: 0.00906 AC XY: 673 AN XY: 74322

African (AFR) AF: 0.0327 AC: 1357 AN: 41490

American (AMR) AF: 0.00269 AC: 41 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67966

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00313 Hom.: 4

Bravo AF: 0.0107

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.64
PhyloP100		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs112458662; hg19: chr20-44594258;