8-41672338-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.5096+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,436 control chromosomes in the GnomAD database, including 799,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72868 hom., cov: 32)

Exomes 𝑓: 1.0 ( 726915 hom. )

Consequence

ANK1
NM_000037.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.169

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 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=-0.91).

BP6

Variant 8-41672338-A-G is Benign according to our data. Variant chr8-41672338-A-G is described in ClinVar as [Benign]. Clinvar id is 261315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41672338-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.5096+16T>C		intron_variant	Intron 38 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.5096+16T>C		intron_variant	Intron 38 of 42	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.978

AC:

148768

AN:

152166

Hom.:

72816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.923

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.995

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.984

GnomAD2 exomes

AF:

0.993

AC:

247996

AN:

249630

AF XY:

0.995

show subpopulations

Gnomad AFR exome

AF:

0.923

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

0.995

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.997

AC:

1457383

AN:

1461150

Hom.:

726915

Cov.:

AF XY:

0.998

AC XY:

725257

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.924

AC:

30928

AN:

33466

American (AMR)

AF:

0.994

AC:

44470

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

26004

AN:

26134

East Asian (EAS)

AF:

1.00

AC:

39693

AN:

39696

South Asian (SAS)

AF:

0.998

AC:

86081

AN:

86242

European-Finnish (FIN)

AF:

1.00

AC:

53045

AN:

53046

Middle Eastern (MID)

AF:

0.994

AC:

5735

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111362

AN:

1111702

Other (OTH)

AF:

0.995

AC:

60065

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

195

390

586

781

976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.978

AC:

148880

AN:

152286

Hom.:

72868

Cov.:

AF XY:

0.979

AC XY:

72861

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.924

AC:

38380

AN:

41558

American (AMR)

AF:

0.991

AC:

15167

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

3456

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5162

AN:

5162

South Asian (SAS)

AF:

0.999

AC:

4817

AN:

4822

European-Finnish (FIN)

AF:

1.00

AC:

10618

AN:

10618

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68004

AN:

68034

Other (OTH)

AF:

0.984

AC:

2076

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.981

Hom.:

8531

Bravo

AF:

0.975

Asia WGS

AF:

0.993

AC:

3455

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:4

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

- -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2021

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.40

(source)

DANN

Benign

0.27

PhyloP100

-0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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8-41672338-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over