16-89282148-T-C

Position:

• chr16-89282148-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013275.6(ANKRD11):​c.4394A>G​(p.His1465Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36534396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.4394A>G	p.His1465Arg	missense_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.4394A>G	p.His1465Arg	missense_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.4394A>G	p.His1465Arg	missense_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.4394A>G	p.His1465Arg	missense_variant	9/13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KBG syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1465 of the ANKRD11 protein (p.His1465Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. ClinVar contains an entry for this variant (Variation ID: 571893). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	.;.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D;D;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.96	D;D;D
Vest4		0.59
MutPred		0.12		Gain of methylation at K1460 (P = 0.043);Gain of methylation at K1460 (P = 0.043);Gain of methylation at K1460 (P = 0.043);
MVP		0.48
MPC		0.52
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.022

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

Other links and lift over

dbSNP: rs960634497; hg19: chr16-89348556;