rs1555529572

Positions:

• chr16-89284911-TTGGTGTGC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_013275.6(ANKRD11):​c.1623_1630del​(p.His542AlafsTer34) variant causes a frameshift change involving the alteration of a 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)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.81

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 12 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 16-89284911-TTGGTGTGC-T is Pathogenic according to our data. Variant chr16-89284911-TTGGTGTGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 520579.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.1623_1630del	p.His542AlafsTer34	frameshift_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.1623_1630del	p.His542AlafsTer34	frameshift_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.1623_1630del	p.His542AlafsTer34	frameshift_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.1623_1630del	p.His542AlafsTer34	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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2014

The c.1623_1630delGCACACCA (p.H542Afs*34) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 8 nucleotides from position 1623 to 1630, causing a translational frameshift with a predicted alternate stop codon after 34 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555529572; hg19: chr16-89351319;