rs797045027

chr16-89284140-TTTTC-T

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.2398_2401del(p.Glu800AsnfsTer62) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,658 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: 0.0000014 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.30

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 16-89284140-TTTTC-T is Pathogenic according to our data. Variant chr16-89284140-TTTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 209131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89284140-TTTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.2398_2401del	p.Glu800AsnfsTer62	frameshift_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.2398_2401del	p.Glu800AsnfsTer62	frameshift_variant	10/14
ANKRD11	NM_001256183.2	c.2398_2401del	p.Glu800AsnfsTer62	frameshift_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.2398_2401del	p.Glu800AsnfsTer62	frameshift_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454658 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 722990

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2012	This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a 20-year-old female with intellectual disability, mild unilateral hearing loss, ptosis, Marcus Gunn pupil, short stature, scoliosis, wrinkled palms, dysmorphisms -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Mar 02, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-02 and interpreted as Pathogenic. Variant was initially reported on 2017-09-23 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with KBG syndrome (MIM#148050). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants are often de novo, and have been reported many times as pathogenic in individuals with KBG syndrome (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has arisen de novo in multiple individuals with KBG syndrome. It has also been reported to segregate within a family with KBG syndrome (ClinVar, Decipher, PMID: 25464108, PMID: 27605097). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 29, 2021	ACMG codes:PVS1, PS4M, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2023	This sequence change creates a premature translational stop signal (p.Glu800Asnfs*62) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with KBG syndrome (PMID: 25464108, 27605097). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209131). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2023	The p.Glu800AsnfsX62 (c.2398_2401delGAAA) variant in ANKRD11 has been reported in 5 probands with KBG syndrome, including as a de novo variant in 2 probands (Goldenberg 2016 PMID: 27605097, Gao 2022 PMID: 35330407, Kim 2015 PMID: 25464108, Parenti 2021 PMID: 33955014, Bestetti 2022 PMID: 35682590). Additionally, it segregated with disease in 3 affected individuals from 2 families (Kim 2015 PMID: 25464108, Parenti 2021 PMID: 33955014). This variant is absent from large population studies (gnomAD v3.2.1, http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID: 209131). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 800 and leads to a premature termination codon 62 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of ANKRD11 is an established disease mechanism in autosomal dominant KBG syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant KBG syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM6_Strong, PM2_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	research	Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano	Nov 01, 2021	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 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: 31703437, 31401500, 32124548, 27605097, 25464108, 27479843, 28135719, 31216405, 26633545, 33955014, 34387732) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute for Human Genetics, University Hospital Essen

Jan 22, 2021

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Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.2398_2401delGAAA (p.E800Nfs*62) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 4 nucleotides from position 2398 to 2401, causing a translational frameshift with a predicted alternate stop codon after 62 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 variant has been reported as a de novo mutation in multiple unrelated individuals with clinical features of KBG syndrome (Goldenberg, 2016; Gao, 2022). In addition, it has been found to segregate with disease in one family (Kim, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Rare genetic intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

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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: rs797045027; hg19: chr16-89350548;