16-89284140-TTTTC-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_013275.6(ANKRD11):c.2398_2401delGAAA(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.30

Publications

5 publications found

Variant links:

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]

ANKRD11 Gene-Disease associations (from GenCC):

KBG syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, Illumina, ClinGen
congenital heart defects, multiple types
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ANKRD11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 209131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ANKRD11	NM_013275.6 link	c.2398_2401delGAAA	p.Glu800AsnfsTer62	frameshift_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2 link	c.2398_2401delGAAA	p.Glu800AsnfsTer62	frameshift_variant	Exon 10 of 14		NP_001243111.1
ANKRD11	NM_001256183.2 link	c.2398_2401delGAAA	p.Glu800AsnfsTer62	frameshift_variant	Exon 9 of 13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10 link	c.2398_2401delGAAA	p.Glu800AsnfsTer62	frameshift_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454658

Hom.:

AF XY:

0.00

AC XY:

AN XY:

722990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

43444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

83678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109912

Other (OTH)

AF:

0.00

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KBG syndrome

Pathogenic:12

Aug 16, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Mar 02, 2018

GenomeConnect - Simons Searchlight

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

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.

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 29, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PVS1, PS4M, PP5

Aug 29, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 22, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: 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: VCV000209131 /PMID: 25464108 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Nov 01, 2021

Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Jul 27, 2012

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 18, 2017

Autoinflammatory diseases unit, CHU de Montpellier

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209131). 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. This variant is not present in population databases (gnomAD no frequency).

Mar 19, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: 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); Variant is present in gnomAD <0.001 for a dominant condition (v4: 2 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories (ClinVar). In addition, it has been reported in de novo individuals with KBG syndrome and has been seen to segregate within an affected family (PMIDs: 25464108, 27605097; DECIPHER); 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). Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease; Loss of function is a known mechanism of disease in this gene and is associated with KBG syndrome (MIM#148050); Variants in this gene are known to have variable expressivity. Intrafamilial variability is commonly reported (PMID: 29258554) - Inheritance information for this variant is not currently available in this individual.

not provided

Pathogenic:4

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 30, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 09, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Global developmental delay

Pathogenic:1

Jan 22, 2021

Institute for Human Genetics, University Hospital Essen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Inborn genetic diseases

Pathogenic:1

Sep 27, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.3

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over