rs28533718

Positions:

• chr8-41717037-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.1320G>A​(p.Pro440=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,124 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (187 hom., cov: 33)
  • Exomes 𝑓: 0.016 (328 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-41717037-C-T is Benign according to our data. Variant chr8-41717037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41717037-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.1320G>A	p.Pro440=	synonymous_variant	13/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.1320G>A	p.Pro440=	synonymous_variant	13/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5596 AN: 152196 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0213 AC: 5353 AN: 251486 Hom.: 123 AF XY: 0.0207 AC XY: 2807 AN XY: 135918

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0286

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0156 AC: 22751 AN: 1461810 Hom.: 328 Cov.: 32 AF XY: 0.0158 AC XY: 11486 AN XY: 727224

Gnomad4 AFR exome AF: 0.0893

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0368 AC: 5599 AN: 152314 Hom.: 187 Cov.: 33 AF XY: 0.0356 AC XY: 2653 AN XY: 74480

Gnomad4 AFR AF: 0.0931

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0208 Hom.: 64

Bravo AF: 0.0377

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 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	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs28533718; hg19: chr8-41574555;