rs534329317

chr16-89282043-TGCTCGTCCCTGTGATGCCGCAGGA-Tchr16-89282043-TGCTCGTCCCTGTGATGCCGCAGGA-TGCTCGTCCCTGTGATGCCGCAGGAGCTCGTCCCTGTGATGCCGCAGGA

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):c.4475_4498del(p.Leu1492_Glu1499del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,613,712 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: ANKRD11 NM_013275.6 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.291

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 Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_013275.6.
• BP6: Variant 16-89282043-TGCTCGTCCCTGTGATGCCGCAGGA-T is Benign according to our data. Variant chr16-89282043-TGCTCGTCCCTGTGATGCCGCAGGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 772792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89282043-TGCTCGTCCCTGTGATGCCGCAGGA-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000434 (66/152238) while in subpopulation SAS AF= 0.00311 (15/4816). AF 95% confidence interval is 0.00192. There are 1 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.4475_4498del	p.Leu1492_Glu1499del	inframe_deletion	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.4475_4498del	p.Leu1492_Glu1499del	inframe_deletion	10/14
ANKRD11	NM_001256183.2	c.4475_4498del	p.Leu1492_Glu1499del	inframe_deletion	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.4475_4498del	p.Leu1492_Glu1499del	inframe_deletion	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000697 AC: 175 AN: 250986 Hom.: 1 AF XY: 0.000869 AC XY: 118 AN XY: 135744

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000499 AC: 730 AN: 1461474 Hom.: 1 AF XY: 0.000600 AC XY: 436 AN XY: 727042

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74432

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000291

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 16, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ANKRD11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs534329317; hg19: chr16-89348451;