16-89281204-C-T

Variant names:

• chr16-89281204-C-T
• rs75362060
• NM_013275.6:c.5338G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):​c.5338G>A​(p.Ala1780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,614,182 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1780G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (34 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.37
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037069619).
• BP6: Variant 16-89281204-C-T is Benign according to our data. Variant chr16-89281204-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 528452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00492 (749/152292) while in subpopulation AMR AF = 0.00902 (138/15306). AF 95% confidence interval is 0.00779. There are 1 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 749 AD gene.

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.5338G>A	p.Ala1780Thr	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.5338G>A	p.Ala1780Thr	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.5338G>A	p.Ala1780Thr	missense	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.5338G>A	p.Ala1780Thr	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.5338G>A	p.Ala1780Thr	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.5338G>A	p.Ala1780Thr	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00494 AC: 1237 AN: 250394 AF XY: 0.00515

Gnomad AFR exome AF: 0.000880

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00556 AC: 8122 AN: 1461890 Hom.: 34 Cov.: 34 AF XY: 0.00571 AC XY: 4150 AN XY: 727244

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00702 AC: 314 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 353 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53416

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5768

European-Non Finnish (NFE) AF: 0.00615 AC: 6843 AN: 1112012

Other (OTH) AF: 0.00550 AC: 332 AN: 60396

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00451 AC XY: 336 AN XY: 74464

African (AFR) AF: 0.00103 AC: 43 AN: 41554

American (AMR) AF: 0.00902 AC: 138 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00698 AC: 475 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00689 Hom.: 14

Bravo AF: 0.00601

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00454 AC: 551

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00966

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	KBG syndrome (3)
-	-	3	not provided (3)
-	-	1	ANKRD11-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.1
DANN	Benign	0.20
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.083
MVP		0.15
MPC		0.082
ClinPred		0.0011	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.024
Mutation Taster		=100/0	polymorphism

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: rs75362060; hg19: chr16-89347612; COSMIC: COSV99968611; COSMIC: COSV99968611;