rs57815524

Variant names:

• chr8-41725743-C-G
• rs57815524
• NM_000037.4:c.612+18G>C

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.612+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00789 in 1,605,156 control chromosomes in the GnomAD database, including 729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (374 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (355 hom.)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.933
• Publications: 2 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-41725743-C-G is Benign according to our data. Variant chr8-41725743-C-G is described in ClinVar as Benign. ClinVar VariationId is 261320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.612+18G>C		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.711+18G>C		intron	N/A	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.612+18G>C		intron	N/A	NP_065209.2	P16157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.612+18G>C		intron	N/A	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.711+18G>C		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.612+18G>C		intron	N/A	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152214 Hom.: 366 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0108 AC: 2540 AN: 235768 AF XY: 0.00794

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.00924

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000265

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00461 AC: 6691 AN: 1452824 Hom.: 355 Cov.: 32 AF XY: 0.00411 AC XY: 2969 AN XY: 722376

African (AFR) AF: 0.139 AC: 4641 AN: 33312

American (AMR) AF: 0.0108 AC: 477 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.000693 AC: 18 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.000470 AC: 40 AN: 85132

European-Finnish (FIN) AF: 0.000139 AC: 7 AN: 50466

Middle Eastern (MID) AF: 0.0122 AC: 51 AN: 4168

European-Non Finnish (NFE) AF: 0.000665 AC: 738 AN: 1109940

Other (OTH) AF: 0.0120 AC: 719 AN: 59978

GnomAD4 genome AF: 0.0392 AC: 5966 AN: 152332 Hom.: 374 Cov.: 33 AF XY: 0.0384 AC XY: 2863 AN XY: 74500

African (AFR) AF: 0.133 AC: 5519 AN: 41564

American (AMR) AF: 0.0204 AC: 313 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68036

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

Alfa AF: 0.0220 Hom.: 36

Bravo AF: 0.0457

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary spherocytosis type 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.30
DANN	Benign	0.74
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57815524; hg19: chr8-41583261;