8-41684575-G-A

Position:

• chr8-41684575-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000037.4(ANK1):​c.4506C>T​(p.Arg1502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,613,766 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 33)
  • Exomes 𝑓: 0.029 (688 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.368

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=-0.62).
• BP6: Variant 8-41684575-G-A is Benign according to our data. Variant chr8-41684575-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41684575-G-A is described in Lovd as [Benign]. Variant chr8-41684575-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.368 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0205 (3116/152338) while in subpopulation NFE AF= 0.0286 (1948/68038). AF 95% confidence interval is 0.0276. There are 49 homozygotes in gnomad4. There are 1415 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.4506C>T	p.Arg1502=	synonymous_variant	37/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.4506C>T	p.Arg1502=	synonymous_variant	37/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3117 AN: 152222 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0227 AC: 5697 AN: 250946 Hom.: 85 AF XY: 0.0222 AC XY: 3016 AN XY: 135698

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0287 AC: 41989 AN: 1461428 Hom.: 688 Cov.: 32 AF XY: 0.0282 AC XY: 20479 AN XY: 727028

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.0315

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0205 AC: 3116 AN: 152338 Hom.: 49 Cov.: 33 AF XY: 0.0190 AC XY: 1415 AN XY: 74492

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0264 Hom.: 86

Bravo AF: 0.0209

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0258

EpiControl AF: 0.0251

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

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	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.62
CADD	Benign	4.1
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs34265667; hg19: chr8-41542093;