rs17661203

Variant names:

• chr8-41723118-T-C
• rs17661203
• NM_000037.4:c.909+7A>G

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: 0.270
• Publications: 4 publications found

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]

ANK1 Gene-Disease associations (from GenCC):

• hereditary spherocytosis

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hereditary spherocytosis type 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 261322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000037.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.909+7A>G		splice_region intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.1008+7A>G		splice_region intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.909+7A>G		splice_region intron	N/A	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.909+7A>G		splice_region intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.1008+7A>G		splice_region intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.909+7A>G		splice_region intron	N/A	ENSP00000339620.4

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

GnomAD2 exomes AF: 0.0460 AC: 11570 AN: 251472 AF XY: 0.0432

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 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

African (AFR) AF: 0.0210 AC: 702 AN: 33476

American (AMR) AF: 0.0672 AC: 3006 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 691 AN: 26132

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39700

South Asian (SAS) AF: 0.0150 AC: 1292 AN: 86254

European-Finnish (FIN) AF: 0.0719 AC: 3843 AN: 53418

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5768

European-Non Finnish (NFE) AF: 0.0599 AC: 66642 AN: 1111734

Other (OTH) AF: 0.0469 AC: 2831 AN: 60390

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

African (AFR) AF: 0.0205 AC: 852 AN: 41554

American (AMR) AF: 0.0401 AC: 613 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3466

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4824

European-Finnish (FIN) AF: 0.0767 AC: 814 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0555 AC: 3776 AN: 68016

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0477 Hom.: 168

Bravo AF: 0.0390

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0466

EpiControl AF: 0.0519

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary spherocytosis type 1 (4)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.44
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.0
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs17661203; hg19: chr8-41580636;