rs1555852178

Variant names:

• chr20-45971258-G-GGCCTCT
• rs1555852178
• NM_022095.4:c.147_152dupAGAGGC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_022095.4(ZNF335):​c.147_152dupAGAGGC​(p.Ala51_Asp52insGluAla) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000922 in 1,409,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: ZNF335 NM_022095.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.49
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_022095.4.

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.147_152dupAGAGGC	p.Ala51_Asp52insGluAla	disruptive_inframe_insertion	Exon 2 of 28	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.147_152dupAGAGGC	p.Ala51_Asp52insGluAla	disruptive_inframe_insertion	Exon 2 of 28	ENSP00000325326.2	Q9H4Z2-1
	ZNF335	ENST00000944756.1		c.147_152dupAGAGGC	p.Ala51_Asp52insGluAla	disruptive_inframe_insertion	Exon 2 of 28	ENSP00000614815.1
	ZNF335	ENST00000862676.1		c.147_152dupAGAGGC	p.Ala51_Asp52insGluAla	disruptive_inframe_insertion	Exon 1 of 27	ENSP00000532735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000244 AC: 4 AN: 164078 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000299

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.00000922 AC: 13 AN: 1409766 Hom.: 0 Cov.: 35 AF XY: 0.00000860 AC XY: 6 AN XY: 698004

African (AFR) AF: 0.0000925 AC: 3 AN: 32426

American (AMR) AF: 0.00 AC: 0 AN: 38598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37176

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39412

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5690

European-Non Finnish (NFE) AF: 0.00000458 AC: 5 AN: 1090674

Other (OTH) AF: 0.0000341 AC: 2 AN: 58640

GnomAD4 genome Cov.: 33

Alfa AF: 0.000102 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

Splicing

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

Other links and lift over

dbSNP: rs1555852178; hg19: chr20-44599897;