16-89282969-G-C

Variant names:

• chr16-89282969-G-C
• rs62000377
• NM_013275.6:c.3573C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013275.6(ANKRD11):​c.3573C>G​(p.Ala1191Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,612,760 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1191A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (147 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1440 hom.)
• Consequence: ANKRD11 NM_013275.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.69
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• KBG syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-89282969-G-C is Benign according to our data. Variant chr16-89282969-G-C is described in ClinVar as Benign. ClinVar VariationId is 380365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	NM_013275.6	MANE Select	c.3573C>G	p.Ala1191Ala	synonymous	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.3573C>G	p.Ala1191Ala	synonymous	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.3573C>G	p.Ala1191Ala	synonymous	Exon 9 of 13	NP_001243112.1	Q6UB99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.3573C>G	p.Ala1191Ala	synonymous	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.3573C>G	p.Ala1191Ala	synonymous	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.3573C>G	p.Ala1191Ala	synonymous	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5120 AN: 151192 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.00730

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0255

GnomAD2 exomes AF: 0.0401 AC: 10055 AN: 250702 AF XY: 0.0393

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.0668

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0433

GnomAD4 exome AF: 0.0396 AC: 57861 AN: 1461448 Hom.: 1440 Cov.: 37 AF XY: 0.0386 AC XY: 28045 AN XY: 727052

African (AFR) AF: 0.00624 AC: 209 AN: 33480

American (AMR) AF: 0.0298 AC: 1331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 295 AN: 26136

East Asian (EAS) AF: 0.0627 AC: 2489 AN: 39700

South Asian (SAS) AF: 0.0116 AC: 997 AN: 86258

European-Finnish (FIN) AF: 0.122 AC: 6437 AN: 52978

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.0395 AC: 43936 AN: 1112010

Other (OTH) AF: 0.0352 AC: 2125 AN: 60394

GnomAD4 genome AF: 0.0338 AC: 5121 AN: 151312 Hom.: 147 Cov.: 32 AF XY: 0.0376 AC XY: 2777 AN XY: 73858

African (AFR) AF: 0.00728 AC: 300 AN: 41194

American (AMR) AF: 0.0249 AC: 378 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.0644 AC: 329 AN: 5108

South Asian (SAS) AF: 0.0162 AC: 77 AN: 4746

European-Finnish (FIN) AF: 0.130 AC: 1354 AN: 10448

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0382 AC: 2594 AN: 67854

Other (OTH) AF: 0.0252 AC: 53 AN: 2100

Alfa AF: 0.0248 Hom.: 23

Bravo AF: 0.0252

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.0307

EpiControl AF: 0.0293

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	KBG syndrome (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.011
DANN	Benign	0.29
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62000377; hg19: chr16-89349377; COSMIC: COSV56357490; COSMIC: COSV56357490;