NM_013275.6:c.2409_2412delAAAA

Variant names:

• chr16-89284129-CTTTT-C
• rs886039902
• NM_013275.6:c.2409_2412delAAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_013275.6(ANKRD11):​c.2409_2412delAAAA​(p.Glu805ArgfsTer57) variant causes a frameshift change. 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:3
• Conservation: PhyloP100: 4.98
• Publications: 5 publications found

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

ACMG classification

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 16-89284129-CTTTT-C is Pathogenic according to our data. Variant chr16-89284129-CTTTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.2409_2412delAAAA	p.Glu805ArgfsTer57	frameshift_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.2409_2412delAAAA	p.Glu805ArgfsTer57	frameshift_variant	Exon 10 of 14		NP_001243111.1
ANKRD11	NM_001256183.2	c.2409_2412delAAAA	p.Glu805ArgfsTer57	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	c.2409_2412delAAAA	p.Glu805ArgfsTer57	frameshift_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:2

-

Genome Medicine, Institute for Basic Research in Developmental Disabilities

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KBG syndrome -

Sep 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu805Argfs*57 variant in ANKRD11 has not been reported in patients and is absent from large population studies, though the ability of these studies to ac curately detect indels may be limited. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 805 and leads to a premature termination codon 57 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the ANKRD11 gene is an established disease mecha nism in KBG syndrome. In summary, the p.Glu805Argfs*57 variant in ANKRD11 meets criteria to be classified as likely pathogenic for KBG syndrome in an autosomal dominant manner based on predicted impact to the protein. -

not provided Pathogenic:1

Mar 13, 2023

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30609409, 35970914) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039902; hg19: chr16-89350537;