8-41661944-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000037.4(ANK1):c.5479-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 1,613,258 control chromosomes in the GnomAD database, including 473,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 43847 hom., cov: 31)

Exomes 𝑓: 0.77 ( 429180 hom. )

Consequence

ANK1
NM_000037.4 splice_region, intron

Scores

Splicing: ADA: 0.00003439

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.753

Publications

87 publications found

Variant links:

Genes affected

ANK1 (HGNC:492): (ankyrin 1) Ankyrins are a family of proteins that 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 1, the prototype of this family, was first discovered in the erythrocytes, but since has also been found in brain and muscles. Mutations in erythrocytic ankyrin 1 have been associated in approximately half of all patients with hereditary spherocytosis. Complex patterns of alternative splicing in the regulatory domain, giving rise to different isoforms of ankyrin 1 have been described. Truncated muscle-specific isoforms of ankyrin 1 resulting from usage of an alternate promoter have also been identified. [provided by RefSeq, Dec 2008]

ANK1 Gene-Disease associations (from GenCC):

hereditary spherocytosis
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
hereditary spherocytosis type 1
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ANK1 links:

ENSG00000253389 (HGNC:):

ENSG00000253389 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 8-41661944-A-G is Benign according to our data. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in CliVar as Benign. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.5479-3T>C		splice_region_variant, intron_variant	Intron 40 of 42	ENST00000289734.13	NP_000028.3	P16157-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13 link	c.5479-3T>C		splice_region_variant, intron_variant	Intron 40 of 42	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

115321

AN:

151888

Hom.:

43819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.750

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.743

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.836

Gnomad SAS

AF:

0.799

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.694

Gnomad NFE

AF:

0.759

Gnomad OTH

AF:

0.741

GnomAD2 exomes

AF:

0.777

AC:

194451

AN:

250108

AF XY:

0.777

show subpopulations

Gnomad AFR exome

AF:

0.745

Gnomad AMR exome

AF:

0.807

Gnomad ASJ exome

AF:

0.709

Gnomad EAS exome

AF:

0.835

Gnomad FIN exome

AF:

0.790

Gnomad NFE exome

AF:

0.761

Gnomad OTH exome

AF:

0.773

GnomAD4 exome

AF:

0.766

AC:

1118799

AN:

1461250

Hom.:

429180

Cov.:

AF XY:

0.766

AC XY:

556567

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.750

AC:

25106

AN:

33478

American (AMR)

AF:

0.801

AC:

35839

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.711

AC:

18574

AN:

26136

East Asian (EAS)

AF:

0.820

AC:

32529

AN:

39692

South Asian (SAS)

AF:

0.800

AC:

68991

AN:

86258

European-Finnish (FIN)

AF:

0.795

AC:

42095

AN:

52980

Middle Eastern (MID)

AF:

0.714

AC:

4117

AN:

5768

European-Non Finnish (NFE)

AF:

0.760

AC:

845207

AN:

1111834

Other (OTH)

AF:

0.767

AC:

46341

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16656

33311

49967

66622

83278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20450

40900

61350

81800

102250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.759

AC:

115403

AN:

152008

Hom.:

43847

Cov.:

AF XY:

0.760

AC XY:

56446

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.749

AC:

31051

AN:

41432

American (AMR)

AF:

0.743

AC:

11357

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2449

AN:

3470

East Asian (EAS)

AF:

0.836

AC:

4317

AN:

5162

South Asian (SAS)

AF:

0.798

AC:

3845

AN:

4818

European-Finnish (FIN)

AF:

0.799

AC:

8447

AN:

10574

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.759

AC:

51611

AN:

67966

Other (OTH)

AF:

0.740

AC:

1553

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1412

2824

4235

5647

7059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.758

Hom.:

130064

Bravo

AF:

0.753

Asia WGS

AF:

0.845

AC:

2939

AN:

3478

EpiCase

AF:

0.738

EpiControl

AF:

0.742

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:5

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spherocytosis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.1

(source)

DANN

Benign

0.53

PhyloP100

0.75

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over