rs1555523386

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_013275.6(ANKRD11):​c.7618C>T​(p.Arg2540Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 3.20
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a region_of_interest Important for protein degradation (size 294) in uniprot entity ANR11_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_013275.6
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD11NM_013275.6 linkc.7618C>T p.Arg2540Trp missense_variant Exon 11 of 13 ENST00000301030.10 NP_037407.4 Q6UB99
ANKRD11NM_001256182.2 linkc.7618C>T p.Arg2540Trp missense_variant Exon 12 of 14 NP_001243111.1 Q6UB99
ANKRD11NM_001256183.2 linkc.7618C>T p.Arg2540Trp missense_variant Exon 11 of 13 NP_001243112.1 Q6UB99

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD11ENST00000301030.10 linkc.7618C>T p.Arg2540Trp missense_variant Exon 11 of 13 5 NM_013275.6 ENSP00000301030.4 Q6UB99

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461242
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726952
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

KBG syndrome Pathogenic:1Uncertain:2
Sep 27, 2023
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 07, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS2_MOD,PS4_SUP,PM2_SUP -

not provided Uncertain:2
Sep 22, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene -

Apr 04, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D;D;.;D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.73
D;D;D;D
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
1.9
L;L;.;L
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-6.8
D;D;.;.
REVEL
Uncertain
0.39
Sift
Pathogenic
0.0
D;D;.;.
Sift4G
Pathogenic
0.0010
D;D;.;.
Polyphen
1.0
D;D;.;D
Vest4
0.86
MutPred
0.50
Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);.;Loss of MoRF binding (P = 0.0475);
MVP
0.84
MPC
3.1
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.72
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1555523386; hg19: chr16-89341317; COSMIC: COSV56359587; COSMIC: COSV56359587; API