8-41744167-C-T

Variant names:

• chr8-41744167-C-T
• rs521184
• NM_000037.4:c.130-10098G>A

Variant summary

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

The NM_000037.4(ANK1):​c.130-10098G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 151,978 control chromosomes in the GnomAD database, including 21,106 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 0.50 (21106 hom., cov: 32)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 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.130-10098G>A		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.229-10098G>A		intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.130-10098G>A		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.130-10098G>A		intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.229-10098G>A		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.130-10098G>A		intron	N/A	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76523 AN: 151860 Hom.: 21104 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.504 AC: 76549 AN: 151978 Hom.: 21106 Cov.: 32 AF XY: 0.504 AC XY: 37431 AN XY: 74290

African (AFR) AF: 0.271 AC: 11229 AN: 41438

American (AMR) AF: 0.545 AC: 8332 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1845 AN: 3470

East Asian (EAS) AF: 0.771 AC: 3984 AN: 5168

South Asian (SAS) AF: 0.560 AC: 2696 AN: 4816

European-Finnish (FIN) AF: 0.509 AC: 5356 AN: 10528

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.607 AC: 41284 AN: 67958

Other (OTH) AF: 0.516 AC: 1088 AN: 2110

Alfa AF: 0.577 Hom.: 108657

Bravo AF: 0.499

Asia WGS AF: 0.617 AC: 2146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.60
DANN	Benign	0.48
PhyloP100		-1.5
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: rs521184; hg19: chr8-41601685;