rs543817

Variant names:

• chr8-41653638-A-C
• rs543817
• NM_000037.4:c.*2152T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-41653638-A-C
• chr8-41653638-A-T

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.*2152T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.985 in 152,592 control chromosomes in the GnomAD database, including 74,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (73940 hom., cov: 33)
  • Exomes 𝑓: 1.0 (148 hom.)
• Consequence: ANK1 NM_000037.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0400
• Publications: 3 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=-0.88).
• BP6: Variant 8-41653638-A-C is Benign according to our data. Variant chr8-41653638-A-C is described in ClinVar as Benign. ClinVar VariationId is 362954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.*2152T>G		3_prime_UTR	Exon 43 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.*2089T>G		3_prime_UTR	Exon 43 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.*2089T>G		3_prime_UTR	Exon 42 of 42	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.*2152T>G		3_prime_UTR	Exon 43 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.*2089T>G		3_prime_UTR	Exon 43 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.*2089T>G		3_prime_UTR	Exon 42 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149920 AN: 152176 Hom.: 73884 Cov.: 33

Gnomad AFR AF: 0.949

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.988

GnomAD4 exome AF: 0.997 AC: 297 AN: 298 Hom.: 148 Cov.: 0 AF XY: 1.00 AC XY: 214 AN XY: 214

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 154 AN: 154

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 1.00 AC: 122 AN: 122

Other (OTH) AF: 1.00 AC: 12 AN: 12

GnomAD4 genome AF: 0.985 AC: 150035 AN: 152294 Hom.: 73940 Cov.: 33 AF XY: 0.986 AC XY: 73394 AN XY: 74448

African (AFR) AF: 0.949 AC: 39449 AN: 41570

American (AMR) AF: 0.994 AC: 15227 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3461 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5140 AN: 5140

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10632 AN: 10632

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68001 AN: 68018

Other (OTH) AF: 0.988 AC: 2089 AN: 2114

Alfa AF: 0.993 Hom.: 11168

Bravo AF: 0.983

Asia WGS AF: 0.997 AC: 3467 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.9
DANN	Benign	0.71
PhyloP100		0.040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs543817; hg19: chr8-41511157;