rs886041125
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.1903_1907del(p.Lys635GlnfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ANKRD11
NM_013275.6 frameshift
NM_013275.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.81
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]
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ACMG classification
Classification made for transcript
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 16-89284634-GTGTTT-G is Pathogenic according to our data. Variant chr16-89284634-GTGTTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89284634-GTGTTT-G is described in Lovd as [Pathogenic]. Variant chr16-89284634-GTGTTT-G is described in Lovd as [Likely_pathogenic]. Variant chr16-89284634-GTGTTT-G is described in Lovd as [Pathogenic]. Variant chr16-89284634-GTGTTT-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ANKRD11 | NM_013275.6 | c.1903_1907del | p.Lys635GlnfsTer26 | frameshift_variant | 9/13 | ENST00000301030.10 | NP_037407.4 | |
| ANKRD11 | NM_001256182.2 | c.1903_1907del | p.Lys635GlnfsTer26 | frameshift_variant | 10/14 | NP_001243111.1 | ||
| ANKRD11 | NM_001256183.2 | c.1903_1907del | p.Lys635GlnfsTer26 | frameshift_variant | 9/13 | NP_001243112.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ANKRD11 | ENST00000301030.10 | c.1903_1907del | p.Lys635GlnfsTer26 | frameshift_variant | 9/13 | 5 | NM_013275.6 | ENSP00000301030 | P1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727230
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GnomAD4 genome 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:35Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:21Other:1
| 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, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Aug 01, 2017 | De novo LOF variant in a patient with feeding difficulties, short stature, microcephaly, moderate to severe ID, facial freckling. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 05, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | Aug 31, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Mar 08, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Oct 26, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Nov 02, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 01, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Dec 15, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279678 / PMID: 25413698). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, University of Torino | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 9 of 13 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a heterozygous familial and de novo change in patients with KBG syndrome (PMID: 27667800, 28449295, 27605097, 25533962, 28250421). The c.1903_1907del (p.Lys635GlnfsTer26) variant is absent from the gnomAD population database and thus is presumed to be rare. This result was confirmed by orthogonal testing. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1903_1907del (p.Lys635GlnfsTer26) variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 21, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM6 moderated - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 12, 2023 | This sequence change creates a premature translational stop signal (p.Lys635Glnfs*26) 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: 25533962, 25833229, 27605097, 27667800, 28250421, 28449295; Invitae). 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: 279678). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 08, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 27, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Lab, CHRU Brest | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Mar 11, 2019 | [ACMG/AMP: PVS1, PS2, PM2, PS4_Moderate, PP1, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability is commonly reported (PMID: 29258554). (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) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than ten individuals, including de novo events (ClinVar, DECIPHER, PMID: 36446582). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | ANKRD11: PS2:Very Strong, PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 23, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2022 | 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27605097, 25833229, 28191890, 29158550, 32581362, 25413698, 25424714, 27667800, 25533962, 25363768, 28250421, 28449295, 28135719, 29530238, 31332282, 33048330, 32124548, 32371413, 31981491, 33955014, 33767182) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Aug 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Intellectual disability Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | May 12, 2021 | de novo truncating variant absent from gnomAD. ALready pathogenic in ClinVar - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Dec 01, 2016 | - - |
Global developmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Institute for Human Genetics, University Hospital Essen | Jan 22, 2021 | - - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2016 | - - |
Ptosis;C0018777:Conductive hearing impairment;C0431664:Unilateral cryptorchidism;C0557874:Global developmental delay;C1843108:Short palm;C1848673:Short foot;C1850049:Clinodactyly of the 5th finger;C3714756:Intellectual disability Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Rare genetic intellectual disability Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
ANKRD11-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | The ANKRD11 c.1903_1907del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys635Glnfs*26). This variant has been reported as a recurrent causative variant for KBG Syndrome (Walz et al. 2015. PubMed ID: 25413698; Low et al. 2016. PubMed ID: 27667800; Miyatake et al. 2017. PubMed ID: 28250421; Gnazzo et al. 2020. PubMed ID: 32124548). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Conductive hearing impairment;C0036572:Seizure;C0424503:Abnormal facial shape;C0454644:Delayed speech and language development;C0557874:Global developmental delay Pathogenic:1
| Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at