rs72638959

Positions:

• chr8-41661785-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000037.4(ANK1):​c.5544+91C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,613,130 control chromosomes in the GnomAD database, including 117 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 0.0080 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (105 hom.)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0710

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-41661785-G-A is Benign according to our data. Variant chr8-41661785-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261318.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr8-41661785-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.5544+91C>T		intron_variant		ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.5544+91C>T		intron_variant		1	NM_000037.4	ENSP00000289734	A2
	ENST00000522388.1	n.719+76G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152188 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00891 AC: 2225 AN: 249594 Hom.: 36 AF XY: 0.00891 AC XY: 1204 AN XY: 135146

Gnomad AFR exome AF: 0.00199

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.00980

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00946 AC: 13820 AN: 1460824 Hom.: 105 Cov.: 75 AF XY: 0.00915 AC XY: 6651 AN XY: 726798

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0406

Gnomad4 NFE exome AF: 0.00986

Gnomad4 OTH exome AF: 0.00772

GnomAD4 genome AF: 0.00804 AC: 1225 AN: 152306 Hom.: 12 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74468

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.00894

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00810 Hom.: 10

Bravo AF: 0.00502

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ANK1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2023	BS1, BP4, BP7 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 86/13006=0.6% -

Hereditary spherocytosis type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.92
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72638959; hg19: chr8-41519303;