rs4737009

Variant names:

• chr8-41772887-G-A
• rs4737009
• NM_000037.4:c.28-14750C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-41772887-G-A
• chr8-41772887-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000037.4(ANK1):​c.28-14750C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 151,990 control chromosomes in the GnomAD database, including 9,828 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9828 hom., cov: 32)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 62 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 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.28-14750C>T		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.127-14750C>T		intron	N/A	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.28-14750C>T		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.28-14750C>T		intron	N/A	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.127-14750C>T		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.28-14750C>T		intron	N/A	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50409 AN: 151872 Hom.: 9806 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.289

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.332 AC: 50489 AN: 151990 Hom.: 9828 Cov.: 32 AF XY: 0.330 AC XY: 24501 AN XY: 74292

African (AFR) AF: 0.539 AC: 22316 AN: 41420

American (AMR) AF: 0.259 AC: 3952 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3460

East Asian (EAS) AF: 0.507 AC: 2607 AN: 5142

South Asian (SAS) AF: 0.166 AC: 801 AN: 4812

European-Finnish (FIN) AF: 0.257 AC: 2720 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16434 AN: 67970

Other (OTH) AF: 0.291 AC: 613 AN: 2108

Alfa AF: 0.273 Hom.: 25309

Bravo AF: 0.345

Asia WGS AF: 0.323 AC: 1124 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		0.0050
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: rs4737009; hg19: chr8-41630405;