19-9296092-CAT-C

Variant names:

• chr19-9296092-CAT-C
• rs2066284895
• NM_198535.3:c.1310_1311delAT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_198535.3(ZNF699):​c.1310_1311delAT​(p.His437ArgfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000411 in 1,458,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF699 NM_198535.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.16

Genes affected

ZNF699 (HGNC:24750): (zinc finger protein 699) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.321 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-9296092-CAT-C is Pathogenic according to our data. Variant chr19-9296092-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2584361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF699	NM_198535.3	c.1310_1311delAT	p.His437ArgfsTer11	frameshift_variant	Exon 6 of 6	ENST00000591998.6	NP_940937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF699	ENST00000591998.6	c.1310_1311delAT	p.His437ArgfsTer11	frameshift_variant	Exon 6 of 6	5	NM_198535.3	ENSP00000467723.1
ZNF699	ENST00000308650.4	c.1310_1311delAT	p.His437ArgfsTer11	frameshift_variant	Exon 5 of 5	1		ENSP00000311596.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458688 Hom.: 0 AF XY: 0.00000551 AC XY: 4 AN XY: 725578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DEGCAGS syndrome Pathogenic:2

Aug 26, 2022

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2022

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This c.1310_1311del (p.His437fs) homozygous two-base pair deletion in exon 6 of the ZNF699 gene detected in proband. It is expected in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 437 (p.H437Rfs*11). This ZNF699 variant has been classified as likely pathogenic according to the ACMG/ AMP guidelines (PVS1, PM2,PS4,PP5) -

Computational scores

Source: dbNSFP v4.3

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: rs2066284895; hg19: chr19-9406768;