rs115797011

Variant summary

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

The NM_013275.6(ANKRD11):c.1844C>T(p.Ala615Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,842 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A615T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.00300

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=0.011075228).

BP6

Variant 16-89284698-G-A is Benign according to our data. Variant chr16-89284698-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1298683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000175 (256/1461658) while in subpopulation SAS AF= 0.000533 (46/86258). AF 95% confidence interval is 0.000411. There are 1 homozygotes in gnomad4_exome. There are 141 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.

BS2

High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ANKRD11	NM_013275.6 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	10/14
ANKRD11	NM_001256183.2 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000248

AC:

AN:

249500

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135456

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000175

AC:

256

AN:

1461658

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000217

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000360

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KBG syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

ANKRD11: BP4 -

ANKRD11-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.79

Cadd

Benign

0.013

Dann

Benign

0.75

DEOGEN2

Benign

0.094

T;T;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.053

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.83

N;N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Benign

0.041

Sift

Benign

0.61

T;T;.;.

Sift4G

Benign

0.38

T;T;.;.

Polyphen

0.0030

B;B;B;.

Vest4

0.057

MVP

0.30

MPC

0.084

ClinPred

0.0096

GERP RS

-9.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.016

gMVP

0.0064

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