chr10-60075299-G-A

Position:

chr10-60075299-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_020987.5(ANK3):c.5582C>T(p.Thr1861Met) variant causes a missense change. The variant allele was found at a frequency of 0.00431 in 1,614,154 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 17 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 5.50

Variant links:

Genes affected

ANK3 (HGNC:494): (ankyrin 3) Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ANK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK3. . Gene score misZ 2.7937 (greater than the threshold 3.09). Trascript score misZ 5.3471 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, Tourette syndrome, intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.006896615).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00447 (6529/1461808) while in subpopulation NFE AF= 0.00545 (6057/1111972). AF 95% confidence interval is 0.00533. There are 17 homozygotes in gnomad4_exome. There are 3148 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5 linkuse as main transcript	c.5582C>T	p.Thr1861Met	missense_variant	37/44	ENST00000280772.7	NP_066267.2	Q12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 linkuse as main transcript	c.5582C>T	p.Thr1861Met	missense_variant	37/44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00484

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00259

AC:

647

AN:

250042

Hom.:

AF XY:

0.00239

AC XY:

323

AN XY:

135176

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00447

AC:

6529

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

3148

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.00545

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00285

AC:

434

AN:

152346

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00484

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00401

Hom.:

Bravo

AF:

0.00285

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00268

AC:

325

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Pathogenic:1Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 15, 2022	Functional studies proved missense was disruptive (PMID: 31451636). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ANK3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 24, 2016

- -

ANK3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.0038

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.021

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

REVEL

Benign

0.080

Sift

Uncertain

0.0030

Polyphen

0.11

Vest4

0.17

MVP

0.59

MPC

0.36

ClinPred

0.032

GERP RS

4.7

Varity_R

0.094

gMVP

0.47

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over