8-41661944-A-G

Position:

• chr8-41661944-A-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.5479-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 1,613,258 control chromosomes in the GnomAD database, including 473,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43847 hom., cov: 31)
  • Exomes 𝑓: 0.77 (429180 hom.)
• Consequence: ANK1 NM_000037.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003439
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.753

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]

ENSG00000253389 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-41661944-A-G is Benign according to our data. Variant chr8-41661944-A-G is described in ClinVar as [Benign]. Clinvar id is 261317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41661944-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.5479-3T>C		splice_region_variant, intron_variant		ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.5479-3T>C		splice_region_variant, intron_variant		1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115321 AN: 151888 Hom.: 43819 Cov.: 31

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.741

GnomAD3 exomes AF: 0.777 AC: 194451 AN: 250108 Hom.: 75884 AF XY: 0.777 AC XY: 105147 AN XY: 135342

Gnomad AFR exome AF: 0.745

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.803

Gnomad FIN exome AF: 0.790

Gnomad NFE exome AF: 0.761

Gnomad OTH exome AF: 0.773

GnomAD4 exome AF: 0.766 AC: 1118799 AN: 1461250 Hom.: 429180 Cov.: 72 AF XY: 0.766 AC XY: 556567 AN XY: 726920

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 0.801

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.820

Gnomad4 SAS exome AF: 0.800

Gnomad4 FIN exome AF: 0.795

Gnomad4 NFE exome AF: 0.760

Gnomad4 OTH exome AF: 0.767

GnomAD4 genome AF: 0.759 AC: 115403 AN: 152008 Hom.: 43847 Cov.: 31 AF XY: 0.760 AC XY: 56446 AN XY: 74292

Gnomad4 AFR AF: 0.749

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.836

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.799

Gnomad4 NFE AF: 0.759

Gnomad4 OTH AF: 0.740

Alfa AF: 0.754 Hom.: 48242

Bravo AF: 0.753

Asia WGS AF: 0.845 AC: 2939 AN: 3478

EpiCase AF: 0.738

EpiControl AF: 0.742

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:5

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	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.1
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0020
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: rs515071; hg19: chr8-41519462; COSMIC: COSV55889057; COSMIC: COSV55889057;