rs145906515

Variant names:

• chr16-89281033-G-A
• rs145906515
• NM_013275.6:c.5509C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-89281033-G-A
• chr16-89281033-G-T

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.5509C>T​(p.Pro1837Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,598,712 control chromosomes in the GnomAD database, including 41 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. P1837L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (30 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.906
• Publications: 6 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=0.0031891763).
• BP6: Variant 16-89281033-G-A is Benign according to our data. Variant chr16-89281033-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 589488.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 = 0.004 (610/152330) while in subpopulation AMR AF = 0.00934 (143/15308). AF 95% confidence interval is 0.00809. There are 11 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 610 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.5509C>T	p.Pro1837Ser	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.5509C>T	p.Pro1837Ser	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.5509C>T	p.Pro1837Ser	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.5509C>T	p.Pro1837Ser	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.5509C>T	p.Pro1837Ser	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.5509C>T	p.Pro1837Ser	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152212 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00414 AC: 1000 AN: 241528 AF XY: 0.00397

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00323 AC: 4675 AN: 1446382 Hom.: 30 Cov.: 34 AF XY: 0.00332 AC XY: 2383 AN XY: 717636

African (AFR) AF: 0.00124 AC: 41 AN: 32936

American (AMR) AF: 0.00498 AC: 215 AN: 43204

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 357 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00218 AC: 185 AN: 84806

European-Finnish (FIN) AF: 0.00477 AC: 252 AN: 52794

Middle Eastern (MID) AF: 0.0325 AC: 185 AN: 5696

European-Non Finnish (NFE) AF: 0.00284 AC: 3136 AN: 1102564

Other (OTH) AF: 0.00510 AC: 304 AN: 59628

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152330 Hom.: 11 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74478

African (AFR) AF: 0.000746 AC: 31 AN: 41568

American (AMR) AF: 0.00934 AC: 143 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10626

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68034

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00463 Hom.: 4

Bravo AF: 0.00385

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00388 AC: 471

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	KBG syndrome (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	0.081
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.91
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.019
Sift	Benign	0.38	T
Sift4G	Benign	0.81	T
Polyphen		0.0020	B
Vest4		0.056
MVP		0.21
MPC		0.099
ClinPred		0.0025	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
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: rs145906515; hg19: chr16-89347441;