rs10093583

Positions:

• chr8-41690485-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000037.4(ANK1):​c.3973A>G​(p.Met1325Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,144 control chromosomes in the GnomAD database, including 607 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (285 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (322 hom.)
• Consequence: ANK1 NM_000037.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0012792349).
• BP6: Variant 8-41690485-T-C is Benign according to our data. Variant chr8-41690485-T-C is described in ClinVar as [Benign]. Clinvar id is 261307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41690485-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.3973A>G	p.Met1325Val	missense_variant	32/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.3973A>G	p.Met1325Val	missense_variant	32/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5777 AN: 152156 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0135 AC: 3392 AN: 251442 Hom.: 129 AF XY: 0.0111 AC XY: 1512 AN XY: 135904

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00935 AC: 13669 AN: 1461870 Hom.: 322 Cov.: 33 AF XY: 0.00889 AC XY: 6468 AN XY: 727238

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.00658

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0380 AC: 5784 AN: 152274 Hom.: 285 Cov.: 33 AF XY: 0.0369 AC XY: 2747 AN XY: 74462

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0132 Hom.: 127

Bravo AF: 0.0434

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.118 AC: 518

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.0152 AC: 1842

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00693

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Spherocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.21	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.033
MPC		0.30
ClinPred		0.016	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs10093583; hg19: chr8-41548003;