rs61758865

Positions:

• chr8-41715664-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000037.4(ANK1):​c.1590C>T​(p.Ala530Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,460 control chromosomes in the GnomAD database, including 151 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 0.0064 (5 hom., cov: 33)
  • Exomes 𝑓: 0.011 (146 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.104

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 8-41715664-G-A is Benign according to our data. Variant chr8-41715664-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261292.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.1590C>T	p.Ala530Ala	synonymous_variant	14/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.1590C>T	p.Ala530Ala	synonymous_variant	14/43	1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 980 AN: 152216 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00611 AC: 1536 AN: 251220 Hom.: 17 AF XY: 0.00577 AC XY: 783 AN XY: 135810

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.0111 AC: 16259 AN: 1461126 Hom.: 146 Cov.: 32 AF XY: 0.0106 AC XY: 7713 AN XY: 726868

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.00728

GnomAD4 genome AF: 0.00643 AC: 980 AN: 152334 Hom.: 5 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74486

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00906 Hom.: 4

Bravo AF: 0.00652

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.0117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2023	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	ANK1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Spherocytosis Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.6
DANN	Benign	0.80
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: rs61758865; hg19: chr8-41573182;