16-89268518-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_013275.6(ANKRD11):c.7952T>C(p.Met2651Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000697 in 1,290,540 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2651I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a region_of_interest Important for protein degradation (size 294) in uniprot entity ANR11_HUMAN there are 35 pathogenic changes around while only 4 benign (90%) in NM_013275.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.34369123).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.7952T>C	p.Met2651Thr	missense_variant	13/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.7952T>C	p.Met2651Thr	missense_variant	14/14
ANKRD11	NM_001256183.2	c.7952T>C	p.Met2651Thr	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7952T>C	p.Met2651Thr	missense_variant	13/13	5	NM_013275.6	P1
	ENST00000602042.1	n.415A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.0000589 AC: 9 AN: 152784 Hom.: 0 AF XY: 0.0000489 AC XY: 4 AN XY: 81788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000697 AC: 9 AN: 1290540 Hom.: 0 Cov.: 20 AF XY: 0.00000625 AC XY: 4 AN XY: 639692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000197

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: 0.00000102

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

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

Invitae

Jul 01, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2651 of the ANKRD11 protein (p.Met2651Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	23
Dann	Benign	0.62
DEOGEN2	Uncertain	0.69	D;D;.;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D;D;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;.;.
Polyphen		0.30	B;B;.;B
Vest4		0.83
MutPred		0.35		Gain of glycosylation at M2651 (P = 0.0081);Gain of glycosylation at M2651 (P = 0.0081);.;Gain of glycosylation at M2651 (P = 0.0081);
MVP		0.89
MPC		3.2
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.66
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

LitVar

Other links and lift over

dbSNP: rs1448454894; hg19: chr16-89334926;