rs34664882

Positions:

chr8-41686157-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_Very_StrongBS1BS2

The NM_000037.4(ANK1):c.4385C>T(p.Ala1462Val) variant causes a missense change. The variant allele was found at a frequency of 0.0279 in 1,614,202 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1462A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 48 hom., cov: 33)

Exomes 𝑓: 0.029 ( 688 hom. )

Consequence

ANK1
NM_000037.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.21

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:

ANK1 (HGNC:):

ANK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK1. . Gene score misZ 2.0781 (greater than the threshold 3.09). Trascript score misZ 3.8314 (greater than threshold 3.09). GenCC has associacion of gene with hereditary spherocytosis type 1, hereditary spherocytosis.

BP6

Variant 8-41686157-G-A is Benign according to our data. Variant chr8-41686157-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41686157-G-A is described in Lovd as [Benign]. Variant chr8-41686157-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0204 (3115/152328) while in subpopulation NFE AF= 0.0286 (1947/68030). AF 95% confidence interval is 0.0276. There are 48 homozygotes in gnomad4. There are 1416 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4 linkuse as main transcript	c.4385C>T	p.Ala1462Val	missense_variant	36/43	ENST00000289734.13	NP_000028.3	P16157-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13 linkuse as main transcript	c.4385C>T	p.Ala1462Val	missense_variant	36/43	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3116

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0286

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0227

AC:

5704

AN:

251492

Hom.:

AF XY:

0.0222

AC XY:

3018

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0339

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.0144

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.0287

AC:

41963

AN:

1461874

Hom.:

688

Cov.:

AF XY:

0.0281

AC XY:

20471

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0141

Gnomad4 AMR exome

AF:

0.0313

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0157

Gnomad4 FIN exome

AF:

0.0163

Gnomad4 NFE exome

AF:

0.0322

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0204

AC:

3115

AN:

152328

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1416

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.0138

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.0286

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0267

Hom.:

Bravo

AF:

0.0209

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.0300

AC:

258

ExAC

AF:

0.0219

AC:

2656

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0257

EpiControl

AF:

0.0251

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Spherocytosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

D;.;.

Eigen

Benign

-0.082

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Uncertain

-0.071

MutationAssessor

Uncertain

2.8

M;M;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.041

D;D;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.037

B;B;B

Vest4

0.12

MPC

0.30

ClinPred

0.031

GERP RS

5.5

Varity_R

0.26

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.60

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.60

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over