ENST00000265709.14:c.127-39509T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000265709.14(ANK1):c.127-39509T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,532,402 control chromosomes in the GnomAD database, including 774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.044 ( 310 hom., cov: 32)

Exomes 𝑓: 0.021 ( 464 hom. )

Consequence

ANK1
ENST00000265709.14 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.129

Publications

7 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:

ENSG00000289514 (HGNC:):

ENSG00000289514 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 8-41797646-A-G is Benign according to our data. Variant chr8-41797646-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 507.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.-108T>C		upstream_gene_variant		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.-108T>C		upstream_gene_variant		1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.0436

AC:

6626

AN:

152136

Hom.:

307

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0253

GnomAD4 exome

AF:

0.0208

AC:

28684

AN:

1380148

Hom.:

464

Cov.:

AF XY:

0.0198

AC XY:

13508

AN XY:

682036

show subpopulations

African (AFR)

AF:

0.116

AC:

3475

AN:

29938

American (AMR)

AF:

0.0129

AC:

440

AN:

33994

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

664

AN:

23616

East Asian (EAS)

AF:

0.0000277

AC:

AN:

36050

South Asian (SAS)

AF:

0.00348

AC:

269

AN:

77382

European-Finnish (FIN)

AF:

0.0179

AC:

880

AN:

49108

Middle Eastern (MID)

AF:

0.00824

AC:

AN:

4004

European-Non Finnish (NFE)

AF:

0.0201

AC:

21538

AN:

1069326

Other (OTH)

AF:

0.0244

AC:

1384

AN:

56730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1391

2782

4172

5563

6954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

926

1852

2778

3704

4630

<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:

0.0436

AC:

6645

AN:

152254

Hom.:

310

Cov.:

AF XY:

0.0421

AC XY:

3137

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.112

AC:

4650

AN:

41562

American (AMR)

AF:

0.0235

AC:

359

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5146

South Asian (SAS)

AF:

0.00415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0190

AC:

202

AN:

10618

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0187

AC:

1271

AN:

68014

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

309

619

928

1238

1547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0352

Hom.:

Bravo

AF:

0.0480

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 19, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1, BS1, BP4 -

SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE

Benign:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NG_012820.1(NM_001142446.2):c.127-39509T>C in the ANK1 gene has an allele frequency of 0.112 in African subpopulation in the gnomAD database. 69 homozygous occurrences are observed in the gnomAD database. This variant was reported as -108T-C in a patient, compound heterozygous with V463I (PMID: 8640229). This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2, PM3. -

Jun 01, 1996

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.123, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Hereditary spherocytosis type 1

Benign:1

May 28, 2019

Mendelics

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

-0.85

CADD

Benign

0.10

(source)

DANN

Benign

0.65

PhyloP100

-0.13

PromoterAI

0.037

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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