rs150015583

chr16-89282882-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_013275.6(ANKRD11):c.3660G>A(p.Arg1220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,022 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (8 hom.)
• Consequence: ANKRD11 NM_013275.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.516

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-89282882-C-T is Benign according to our data. Variant chr16-89282882-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89282882-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.516 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00133 (203/152174) while in subpopulation NFE AF= 0.00276 (188/67996). AF 95% confidence interval is 0.00244. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.3660G>A	p.Arg1220=	synonymous_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.3660G>A	p.Arg1220=	synonymous_variant	10/14
ANKRD11	NM_001256183.2	c.3660G>A	p.Arg1220=	synonymous_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.3660G>A	p.Arg1220=	synonymous_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00109 AC: 272 AN: 250650 Hom.: 2 AF XY: 0.000988 AC XY: 134 AN XY: 135602

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000332

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00232 AC: 3390 AN: 1460848 Hom.: 8 Cov.: 36 AF XY: 0.00225 AC XY: 1635 AN XY: 726794

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000382

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74414

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ANKRD11: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -

KBG syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.4
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs150015583; hg19: chr16-89349290; COSMIC: COSV56372574; COSMIC: COSV56372574;