16-89281204-C-T

Position:

chr16-89281204-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013275.6(ANKRD11):c.5338G>A(p.Ala1780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,614,182 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 34 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.37

Variant links:

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]

ANKRD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037069619).

BP6

Variant 16-89281204-C-T is Benign according to our data. Variant chr16-89281204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 528452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89281204-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00492 (749/152292) while in subpopulation AMR AF= 0.00902 (138/15306). AF 95% confidence interval is 0.00779. There are 1 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 749 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6 link	c.5338G>A	p.Ala1780Thr	missense_variant	9/13	ENST00000301030.10	NP_037407.4	Q6UB99
ANKRD11	NM_001256182.2 link	c.5338G>A	p.Ala1780Thr	missense_variant	10/14		NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2 link	c.5338G>A	p.Ala1780Thr	missense_variant	9/13		NP_001243112.1	Q6UB99

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10 link	c.5338G>A	p.Ala1780Thr	missense_variant	9/13	5	NM_013275.6	ENSP00000301030.4		Q6UB99

Frequencies

GnomAD3 genomes

AF:

0.00494

AC:

751

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00903

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00700

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00494

AC:

1237

AN:

250394

Hom.:

AF XY:

0.00515

AC XY:

699

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000880

Gnomad AMR exome

AF:

0.00628

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00225

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00673

Gnomad OTH exome

AF:

0.00572

GnomAD4 exome

AF:

0.00556

AC:

8122

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

4150

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00702

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00615

Gnomad4 OTH exome

AF:

0.00550

GnomAD4 genome

AF:

0.00492

AC:

749

AN:

152292

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00902

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00698

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00742

Hom.:

Bravo

AF:

0.00601

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00454

AC:

551

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KBG syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ANKRD11: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 30, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2017

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

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

0.064

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.1

DANN

Benign

0.20

DEOGEN2

Benign

0.059

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.69

.;.;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.28

N;N;.

REVEL

Benign

0.059

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;B

Vest4

0.083

MVP

0.15

MPC

0.082

ClinPred

0.0011

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.013

gMVP

0.024

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over