8-41690230-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000037.4(ANK1):c.4101C>T(p.Ala1367Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,614,014 control chromosomes in the GnomAD database, including 11,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 4902 hom., cov: 33)

Exomes 𝑓: 0.066 ( 6503 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.74

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 8-41690230-G-A is Benign according to our data. Variant chr8-41690230-G-A is described in ClinVar as [Benign]. Clinvar id is 261309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.4101C>T	p.Ala1367Ala	synonymous_variant	Exon 33 of 43	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.4101C>T	p.Ala1367Ala	synonymous_variant	Exon 33 of 43	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25888

AN:

152084

Hom.:

4888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.474

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0706

Gnomad ASJ

AF:

0.0680

Gnomad EAS

AF:

0.0691

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0296

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0544

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.0797

AC:

20028

AN:

251330

AF XY:

0.0717

show subpopulations

Gnomad AFR exome

AF:

0.484

Gnomad AMR exome

AF:

0.0418

Gnomad ASJ exome

AF:

0.0636

Gnomad EAS exome

AF:

0.0723

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0559

Gnomad OTH exome

AF:

0.0625

GnomAD4 exome

AF:

0.0661

AC:

96602

AN:

1461812

Hom.:

6503

Cov.:

AF XY:

0.0640

AC XY:

46563

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.483

AC:

16161

AN:

33476

American (AMR)

AF:

0.0463

AC:

2070

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

1754

AN:

26136

East Asian (EAS)

AF:

0.0740

AC:

2939

AN:

39700

South Asian (SAS)

AF:

0.0452

AC:

3895

AN:

86256

European-Finnish (FIN)

AF:

0.0340

AC:

1815

AN:

53408

Middle Eastern (MID)

AF:

0.0560

AC:

320

AN:

5716

European-Non Finnish (NFE)

AF:

0.0565

AC:

62807

AN:

1112006

Other (OTH)

AF:

0.0802

AC:

4841

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5492

10985

16477

21970

27462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2566

5132

7698

10264

12830

<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:

0.171

AC:

25955

AN:

152202

Hom.:

4902

Cov.:

AF XY:

0.163

AC XY:

12157

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.475

AC:

19685

AN:

41476

American (AMR)

AF:

0.0705

AC:

1077

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

236

AN:

3472

East Asian (EAS)

AF:

0.0693

AC:

358

AN:

5166

South Asian (SAS)

AF:

0.0458

AC:

221

AN:

4830

European-Finnish (FIN)

AF:

0.0296

AC:

315

AN:

10624

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0544

AC:

3698

AN:

68028

Other (OTH)

AF:

0.131

AC:

277

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

829

1658

2487

3316

4145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.105

Hom.:

1607

Bravo

AF:

0.188

Asia WGS

AF:

0.0920

AC:

319

AN:

3478

EpiCase

AF:

0.0528

EpiControl

AF:

0.0503

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:3

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

not provided

Benign:3

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 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 13, 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

-0.50

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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