rs878855327

Positions:

• chr16-89279749-CG-C
• chr16-89279749-CG-CGG

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.6792del​(p.Ala2265ProfsTer72) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -3.15

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 16-89279749-CG-C is Pathogenic according to our data. Variant chr16-89279749-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 242348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89279749-CG-C is described in Lovd as [Pathogenic]. Variant chr16-89279749-CG-C is described in Lovd as [Likely_pathogenic]. Variant chr16-89279749-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.6792del	p.Ala2265ProfsTer72	frameshift_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.6792del	p.Ala2265ProfsTer72	frameshift_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.6792del	p.Ala2265ProfsTer72	frameshift_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6792del	p.Ala2265ProfsTer72	frameshift_variant	9/13	5	NM_013275.6	ENSP00000301030	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1371814 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 675452

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 26, 2021	The de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant located in exon 9 (of 13) of the ANKRD11 gene alters the wild type translational reading frame and is predicted to result in an absent or truncated protein product. A frameshift variant affecting the same codon and with identical predicted affect on the protein [c.6793delC (p.Ala2265Profs)] has been reported in a patient affected with moderate intellectual disability, seizures, hearing impairment, facial dysmorphism, myalgia, and abnormal biochemical findings (decreased Complex I & V, Complex III near 5% reference; See “additional file2: Table S1” of PMID: 28554332). The variant is absent from gnomAD(v3) database suggesting it is not a common benign allele in the populations represented in that database. Based on the available evidence, the de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant identified in the ANKRD11 gene is reported as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2024

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: 33149276) -

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: rs878855327; hg19: chr16-89346157;