rs61744778

Positions:

• chr16-89282198-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):​c.4344T>C​(p.Tyr1448Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,614,018 control chromosomes in the GnomAD database, including 987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (70 hom., cov: 32)
  • Exomes 𝑓: 0.033 (917 hom.)
• Consequence: ANKRD11 NM_013275.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.91

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-89282198-A-G is Benign according to our data. Variant chr16-89282198-A-G is described in ClinVar as [Benign]. Clinvar id is 585411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89282198-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0248 (3770/152138) while in subpopulation NFE AF= 0.038 (2586/67996). AF 95% confidence interval is 0.0368. There are 70 homozygotes in gnomad4. There are 1785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.4344T>C	p.Tyr1448Tyr	synonymous_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.4344T>C	p.Tyr1448Tyr	synonymous_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.4344T>C	p.Tyr1448Tyr	synonymous_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.4344T>C	p.Tyr1448Tyr	synonymous_variant	9/13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3773 AN: 152020 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00696

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0277 AC: 6967 AN: 251428 Hom.: 118 AF XY: 0.0283 AC XY: 3851 AN XY: 135890

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0333 AC: 48734 AN: 1461880 Hom.: 917 Cov.: 36 AF XY: 0.0330 AC XY: 24004 AN XY: 727240

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0248 AC: 3770 AN: 152138 Hom.: 70 Cov.: 32 AF XY: 0.0240 AC XY: 1785 AN XY: 74378

Gnomad4 AFR AF: 0.00694

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0380

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0311 Hom.: 33

Bravo AF: 0.0240

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0402

ClinVar

Significance: 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	GeneDx	Sep 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KBG syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

This alteration is classified as 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	-0.95
CADD	Benign	0.020
DANN	Benign	0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs61744778; hg19: chr16-89348606;