Genetic Variant NM_013275.6:c.7945G>A (chr16-89268525-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP5_ModerateBP4

The NM_013275.6(ANKRD11):c.7945G>A(p.Val2649Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.95

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:

ENSG00000268218 (HGNC:):

ENSG00000268218 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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;

PP5

Variant 16-89268525-C-T is Pathogenic according to our data. Variant chr16-89268525-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1301284.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.41783652). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6 link	c.7945G>A	p.Val2649Met	missense_variant	Exon 13 of 13	ENST00000301030.10	NP_037407.4	Q6UB99
ANKRD11	NM_001256182.2 link	c.7945G>A	p.Val2649Met	missense_variant	Exon 14 of 14		NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2 link	c.7945G>A	p.Val2649Met	missense_variant	Exon 13 of 13		NP_001243112.1	Q6UB99

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10 link	c.7945G>A	p.Val2649Met	missense_variant	Exon 13 of 13	5	NM_013275.6	ENSP00000301030.4		Q6UB99

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.67e-7

AC:

AN:

1304188

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

645996

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:

0.00000101

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 10, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D;.;D

Eigen

Benign

0.16

Eigen_PC

Benign

0.061

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

.;.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.42

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.6

L;L;.;L

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.5

N;N;.;.

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Uncertain

0.0020

D;D;.;.

Polyphen

0.99

D;D;.;D

Vest4

0.68

MutPred

0.43

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);

MVP

0.90

MPC

3.0

ClinPred

0.95

GERP RS

3.4

Varity_R

0.42

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over