rs797044890

chr16-89275092-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_013275.6(ANKRD11):c.7569+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKRD11 NM_013275.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.77

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.012262262 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-89275092-C-T is Pathogenic according to our data. Variant chr16-89275092-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.7569+1G>A		splice_donor_variant		ENST00000301030.10
ANKRD11	NM_001256182.2	c.7569+1G>A		splice_donor_variant
ANKRD11	NM_001256183.2	c.7569+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7569+1G>A		splice_donor_variant		5	NM_013275.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Sep 05, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-05 and interpreted as Pathogenic. Variant was initially reported on 2014-02-17 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

-

POSITIVE: Relevant Alteration(s) Detected -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2016

TThe c.7569+1G>A pathogenic variant in the ANKRD11 gene has not been published previously as a pathogenic variant nor as a benign variant, to our knowledge. However, this variant has been reported as pathogenic in ClinVar by a different clinical laboratory, although additional evidence is not available (ClinVar SCV000244153.3; Landrum et al., 2015). This splice site variant destroys the canonical splice donor site in intron 10. It is predicted to cause abnormal gene splicing resulting in an in-frame protein product with an abnormal message. The c.7569+1G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.7569+1G>A as a pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044890; hg19: chr16-89341500;