rs886039902

chr16-89284129-CTTTTT-Cchr16-89284129-CTTTTT-CTchr16-89284129-CTTTTT-CTTTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_013275.6(ANKRD11):c.2408_2412del(p.Lys803ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,456,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 4.98

Genes affected

ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89284129-CTTTTT-C is Pathogenic according to our data. Variant chr16-89284129-CTTTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 266033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.2408_2412del	p.Lys803ArgfsTer5	frameshift_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.2408_2412del	p.Lys803ArgfsTer5	frameshift_variant	10/14
ANKRD11	NM_001256183.2	c.2408_2412del	p.Lys803ArgfsTer5	frameshift_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.2408_2412del	p.Lys803ArgfsTer5	frameshift_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456390 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 723966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 09, 2018	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 23, 2022	This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266033). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys803Argfs*5) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421). -
Pathogenic, criteria provided, single submitter	research	Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 09, 2020	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Sep 10, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially reported on 2018-01-09 by GTR ID of laboratory name 506154. The reporting laboratory might also submit to ClinVar. -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Apr 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	May 28, 2020	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ANKRD11: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Dec 12, 2022	PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27667800, 25533962, 28191890, 29224748, 28135719, 32124548) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute for Human Genetics, University Hospital Essen

Jan 22, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.2408_2412delAAAAA (p.K803Rfs*5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 to 2412, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated individuals with clinical features of KBG syndrome (Parenti, 2021; Gnazzo, 2020). Additional heterozygous individuals with ANKRD11 variants have been reported in the literature (Low, 2016; Bestetti, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039902; hg19: chr16-89350537;