rs28533718

Variant names:

• chr8-41717037-C-T
• rs28533718
• NM_000037.4:c.1320G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.1320G>A​(p.Pro440Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,124 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (187 hom., cov: 33)
  • Exomes 𝑓: 0.016 (328 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.31
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-41717037-C-T is Benign according to our data. Variant chr8-41717037-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 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.1320G>A	p.Pro440Pro	synonymous	Exon 13 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.1419G>A	p.Pro473Pro	synonymous	Exon 13 of 43	NP_001135918.1
	ANK1	NM_020476.3		c.1320G>A	p.Pro440Pro	synonymous	Exon 13 of 42	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.1320G>A	p.Pro440Pro	synonymous	Exon 13 of 43	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.1419G>A	p.Pro473Pro	synonymous	Exon 13 of 43	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.1320G>A	p.Pro440Pro	synonymous	Exon 13 of 42	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5596 AN: 152196 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0213 AC: 5353 AN: 251486 AF XY: 0.0207

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0156 AC: 22751 AN: 1461810 Hom.: 328 Cov.: 32 AF XY: 0.0158 AC XY: 11486 AN XY: 727224

African (AFR) AF: 0.0893 AC: 2989 AN: 33474

American (AMR) AF: 0.0112 AC: 499 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 782 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0286 AC: 2468 AN: 86256

European-Finnish (FIN) AF: 0.0128 AC: 685 AN: 53416

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5764

European-Non Finnish (NFE) AF: 0.0127 AC: 14117 AN: 1111944

Other (OTH) AF: 0.0183 AC: 1105 AN: 60396

GnomAD4 genome AF: 0.0368 AC: 5599 AN: 152314 Hom.: 187 Cov.: 33 AF XY: 0.0356 AC XY: 2653 AN XY: 74480

African (AFR) AF: 0.0931 AC: 3868 AN: 41562

American (AMR) AF: 0.0155 AC: 237 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4830

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 999 AN: 68030

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0229 Hom.: 92

Bravo AF: 0.0377

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0135

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Benign	0.69
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs28533718; hg19: chr8-41574555;