NM_020987.5:c.1690-4dupT

Variant names:

• chr10-60196628-G-GA
• rs34796699
• NM_020987.5:c.1690-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020987.5(ANK3):​c.1690-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 132,804 control chromosomes in the GnomAD database, including 956 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (956 hom., cov: 28)
  • Exomes 𝑓: 0.26 (692 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.469
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability-hypotonia-spasticity-sleep disorder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• intellectual disability

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-60196628-G-GA is Benign according to our data. Variant chr10-60196628-G-GA is described in ClinVar as Benign. ClinVar VariationId is 802577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-4dupT		splice_region_variant, intron_variant	Intron 14 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-4dupT		splice_region_variant, intron_variant	Intron 14 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.1690-4dupT		splice_region_variant, intron_variant	Intron 14 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.1672-4dupT		splice_region_variant, intron_variant	Intron 15 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.1690-4_1690-3insT		splice_region_variant, intron_variant	Intron 14 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 14833 AN: 132772 Hom.: 954 Cov.: 28

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0435

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0897

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.313 AC: 35412 AN: 113098 AF XY: 0.318

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.336

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.263 AC: 251852 AN: 956172 Hom.: 692 Cov.: 21 AF XY: 0.267 AC XY: 126959 AN XY: 475462

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.262 AC: 6266 AN: 23934

American (AMR) AF: 0.270 AC: 6996 AN: 25886

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 4575 AN: 16310

East Asian (EAS) AF: 0.282 AC: 7361 AN: 26088

South Asian (SAS) AF: 0.318 AC: 17078 AN: 53750

European-Finnish (FIN) AF: 0.261 AC: 7447 AN: 28488

Middle Eastern (MID) AF: 0.189 AC: 778 AN: 4114

European-Non Finnish (NFE) AF: 0.258 AC: 190677 AN: 738362

Other (OTH) AF: 0.272 AC: 10674 AN: 39240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.112 AC: 14839 AN: 132804 Hom.: 956 Cov.: 28 AF XY: 0.111 AC XY: 7057 AN XY: 63652

African (AFR) AF: 0.188 AC: 6986 AN: 37094

American (AMR) AF: 0.0842 AC: 1097 AN: 13028

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 248 AN: 3186

East Asian (EAS) AF: 0.101 AC: 471 AN: 4668

South Asian (SAS) AF: 0.126 AC: 527 AN: 4198

European-Finnish (FIN) AF: 0.0671 AC: 469 AN: 6994

Middle Eastern (MID) AF: 0.0933 AC: 25 AN: 268

European-Non Finnish (NFE) AF: 0.0790 AC: 4804 AN: 60800

Other (OTH) AF: 0.0997 AC: 178 AN: 1786

Alfa AF: 0.118 Hom.: 21

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34796699; hg19: chr10-61956386; COSMIC: COSV55056648;