rs57815524

chr8-41725743-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000037.4(ANK1):c.612+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00789 in 1,605,156 control chromosomes in the GnomAD database, including 729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (374 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (355 hom.)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.933

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-41725743-C-G is Benign according to our data. Variant chr8-41725743-C-G is described in ClinVar as [Benign]. Clinvar id is 261320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.612+18G>C		intron_variant		ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.612+18G>C		intron_variant		1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152214 Hom.: 366 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0108 AC: 2540 AN: 235768 Hom.: 136 AF XY: 0.00794 AC XY: 1021 AN XY: 128530

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.00924

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.000265

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00461 AC: 6691 AN: 1452824 Hom.: 355 Cov.: 32 AF XY: 0.00411 AC XY: 2969 AN XY: 722376

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.000693

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000470

Gnomad4 FIN exome AF: 0.000139

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0392 AC: 5966 AN: 152332 Hom.: 374 Cov.: 33 AF XY: 0.0384 AC XY: 2863 AN XY: 74500

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0220 Hom.: 36

Bravo AF: 0.0457

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.30
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs57815524; hg19: chr8-41583261;