chr16-89282770-CTT-C

Position:

• chr16-89282770-CTT-C

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.3770_3771del​(p.Lys1257ArgfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.76

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 16-89282770-CTT-C is Pathogenic according to our data. Variant chr16-89282770-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89282770-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.3770_3771del	p.Lys1257ArgfsTer25	frameshift_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.3770_3771del	p.Lys1257ArgfsTer25	frameshift_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.3770_3771del	p.Lys1257ArgfsTer25	frameshift_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.3770_3771del	p.Lys1257ArgfsTer25	frameshift_variant	9/13	5	NM_013275.6	ENSP00000301030	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 06, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory as a de novo finding in a 4-year-old female with delays, hypotonia, anxiety, short stuture, atrial septal defect. -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Jun 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 15, 2020	The de novo c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is the deletion of two nucleotides, resulting in the frameshift of the amino acid 1257/2664 (coding exon 9/13), and is predicted to lead to the premature termination of the protein approximately 25 amino acids downstream of the frameshift. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID: 265324) by two independent clinical labs who state the variant was identified de novo in affected individuals. The c.3770_3771del (p.Lys1257ArgfsTer25) variant has also been reported in the literature in a male with feeding difficulties, short stature, hyperopic astigmatism, hearing loss, and Autism Spectrum Disorder [PMID:28529015], and a female with KBG syndrome [PMID:31703437]. Given its presence de novo in this individual, its deleterious nature, absence in population databases, and observation in multiple affected individuals in the literature, the c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is reported here as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Medicine, Institute for Basic Research in Developmental Disabilities	-	KBG syndrome -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28529015, 31703437, 32124548, 25326635, 28135719) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.3770_3771delAA (p.K1257Rfs*25) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 2 nucleotides from position 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon after 25 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 a de novo event in multiple unrelated individuals with KBG syndrome (Meyer, 2017; Gnazzo, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Rare genetic intellectual disability Pathogenic:1

Likely 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: rs886039477; hg19: chr16-89349178;