chr8-41723118-T-C

Position:

• chr8-41723118-T-C

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.909+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,613,864 control chromosomes in the GnomAD database, including 2,633 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (169 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2464 hom.)
• Consequence: ANK1 NM_000037.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008749
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.270

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-41723118-T-C is Benign according to our data. Variant chr8-41723118-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41723118-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.909+7A>G		splice_region_variant, intron_variant		ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.909+7A>G		splice_region_variant, intron_variant		1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6329 AN: 152150 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0460 AC: 11570 AN: 251472 Hom.: 357 AF XY: 0.0432 AC XY: 5878 AN XY: 135914

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.0700

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0764

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0436

GnomAD4 exome AF: 0.0541 AC: 79127 AN: 1461596 Hom.: 2464 Cov.: 32 AF XY: 0.0523 AC XY: 38011 AN XY: 727118

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.0672

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0719

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0469

GnomAD4 genome AF: 0.0416 AC: 6336 AN: 152268 Hom.: 169 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74446

Gnomad4 AFR AF: 0.0205

Gnomad4 AMR AF: 0.0401

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0767

Gnomad4 NFE AF: 0.0555

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0496 Hom.: 132

Bravo AF: 0.0390

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0466

EpiControl AF: 0.0519

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 17, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

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	-0.78
CADD	Benign	5.1
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs17661203; hg19: chr8-41580636;