rs148243995

Variant names:

• chr16-89281344-G-A
• rs148243995
• NM_013275.6:c.5198C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-89281344-G-A
• chr16-89281344-G-C

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.5198C>T​(p.Ala1733Val) variant causes a missense change. The variant allele was found at a frequency of 0.000272 in 1,612,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. A1733T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.08
• Publications: 3 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=0.008304447).
• BP6: Variant 16-89281344-G-A is Benign according to our data. Variant chr16-89281344-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (197/152316) while in subpopulation AFR AF = 0.00443 (184/41564). AF 95% confidence interval is 0.0039. There are 1 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 197 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.5198C>T	p.Ala1733Val	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.5198C>T	p.Ala1733Val	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.5198C>T	p.Ala1733Val	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.5198C>T	p.Ala1733Val	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.5198C>T	p.Ala1733Val	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.5198C>T	p.Ala1733Val	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000441 AC: 110 AN: 249564 AF XY: 0.000318

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1460100 Hom.: 0 Cov.: 34 AF XY: 0.000153 AC XY: 111 AN XY: 726032

African (AFR) AF: 0.00407 AC: 136 AN: 33428

American (AMR) AF: 0.000515 AC: 23 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110670

Other (OTH) AF: 0.000547 AC: 33 AN: 60330

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74480

African (AFR) AF: 0.00443 AC: 184 AN: 41564

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000616 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	KBG syndrome (3)
-	-	2	not provided (2)
-	-	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	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.092
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.012	D
Polyphen		0.11	B
Vest4		0.13
MVP		0.34
MPC		0.096
ClinPred		0.028	T
GERP RS		4.9
Varity_R		0.032
gMVP		0.038
Mutation Taster		=98/2	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: rs148243995; hg19: chr16-89347752;