NM_013275.6:c.7957G>A

Variant names:

• chr16-89268513-C-T
• NM_013275.6:c.7957G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_013275.6(ANKRD11):​c.7957G>A​(p.Asp2653Asn) 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.12

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]

ENSG00000268218 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.4035934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.7957G>A	p.Asp2653Asn	missense_variant	Exon 13 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.7957G>A	p.Asp2653Asn	missense_variant	Exon 14 of 14		NP_001243111.1
ANKRD11	NM_001256183.2	c.7957G>A	p.Asp2653Asn	missense_variant	Exon 13 of 13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7957G>A	p.Asp2653Asn	missense_variant	Exon 13 of 13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.81e-7 AC: 1 AN: 1280384 Hom.: 0 Cov.: 20 AF XY: 0.00000157 AC XY: 1 AN XY: 634988

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: 0.00

Gnomad4 OTH exome AF: 0.0000185

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Uncertain:1

Apr 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD11 protein function. This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2653 of the ANKRD11 protein (p.Asp2653Asn). -

not provided Uncertain:1

Jul 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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; 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	0.89
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.;T
Eigen	Benign	0.064
Eigen_PC	Benign	-0.064
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;.;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;N;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.021	D;D;.;.
Sift4G	Uncertain	0.0040	D;D;.;.
Polyphen		1.0	D;D;.;D
Vest4		0.71
MutPred		0.38		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);
MVP		0.70
MPC		3.0
ClinPred		0.94	D
GERP RS		3.4
Varity_R		0.15
gMVP		0.92

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.

Other links and lift over

hg19: chr16-89334921;