rs61744778

Variant names:

• chr16-89282198-A-G
• rs61744778
• NM_013275.6:c.4344T>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.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
• 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: Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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 (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 VariationId is 585411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3770 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.4344T>C	p.Tyr1448Tyr	synonymous	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.4344T>C	p.Tyr1448Tyr	synonymous	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.4344T>C	p.Tyr1448Tyr	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.4344T>C	p.Tyr1448Tyr	synonymous	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.4344T>C	p.Tyr1448Tyr	synonymous	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.4344T>C	p.Tyr1448Tyr	synonymous	Exon 9 of 13	ENSP00000495226.1	Q6UB99

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

GnomAD2 exomes AF: 0.0277 AC: 6967 AN: 251428 AF XY: 0.0283

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 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

African (AFR) AF: 0.00618 AC: 207 AN: 33480

American (AMR) AF: 0.0199 AC: 888 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 630 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0187 AC: 1616 AN: 86258

European-Finnish (FIN) AF: 0.0289 AC: 1542 AN: 53416

Middle Eastern (MID) AF: 0.0414 AC: 239 AN: 5766

European-Non Finnish (NFE) AF: 0.0377 AC: 41924 AN: 1112004

Other (OTH) AF: 0.0279 AC: 1684 AN: 60396

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

African (AFR) AF: 0.00694 AC: 288 AN: 41492

American (AMR) AF: 0.0236 AC: 361 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4818

European-Finnish (FIN) AF: 0.0267 AC: 283 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0380 AC: 2586 AN: 67996

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	KBG syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.020
DANN	Benign	0.13
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs61744778; hg19: chr16-89348606;