rs145906515

Positions:

• chr16-89281033-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):​c.5509C>T​(p.Pro1837Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,598,712 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1837P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (30 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.906

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031891763).
• BP6: Variant 16-89281033-G-A is Benign according to our data. Variant chr16-89281033-G-A is described in ClinVar as [Benign]. Clinvar id is 589488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89281033-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.004 (610/152330) while in subpopulation AMR AF= 0.00934 (143/15308). AF 95% confidence interval is 0.00809. There are 11 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 610 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.5509C>T	p.Pro1837Ser	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.5509C>T	p.Pro1837Ser	missense_variant	10/14
ANKRD11	NM_001256183.2	c.5509C>T	p.Pro1837Ser	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.5509C>T	p.Pro1837Ser	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152212 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00414 AC: 1000 AN: 241528 Hom.: 4 AF XY: 0.00397 AC XY: 520 AN XY: 130826

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00323 AC: 4675 AN: 1446382 Hom.: 30 Cov.: 34 AF XY: 0.00332 AC XY: 2383 AN XY: 717636

Gnomad4 AFR exome AF: 0.00124

Gnomad4 AMR exome AF: 0.00498

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.00477

Gnomad4 NFE exome AF: 0.00284

Gnomad4 OTH exome AF: 0.00510

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152330 Hom.: 11 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74478

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00542 Hom.: 2

Bravo AF: 0.00385

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00388 AC: 471

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANKRD11: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 27055092) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

KBG syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 30, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2018

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

This variant is classified as 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.062	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.10	N;N;.
REVEL	Benign	0.019
Sift	Benign	0.38	T;T;.
Sift4G	Benign	0.81	T;T;.
Polyphen		0.0020	B;B;B
Vest4		0.056
MVP		0.21
MPC		0.099
ClinPred		0.0025	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.038

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: rs145906515; hg19: chr16-89347441;