8-41738095-T-C

Variant names:

• chr8-41738095-T-C
• rs516606
• NM_000037.4:c.130-4026A>G

Variant summary

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

The NM_000037.4(ANK1):​c.130-4026A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 152,032 control chromosomes in the GnomAD database, including 24,103 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 0.56 (24103 hom., cov: 32)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 4 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 = 0.75 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.130-4026A>G		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.229-4026A>G		intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.130-4026A>G		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.130-4026A>G		intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.229-4026A>G		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.130-4026A>G		intron	N/A	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84752 AN: 151914 Hom.: 24083 Cov.: 32

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.558 AC: 84809 AN: 152032 Hom.: 24103 Cov.: 32 AF XY: 0.557 AC XY: 41364 AN XY: 74318

African (AFR) AF: 0.459 AC: 19030 AN: 41416

American (AMR) AF: 0.566 AC: 8649 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1872 AN: 3468

East Asian (EAS) AF: 0.770 AC: 3980 AN: 5172

South Asian (SAS) AF: 0.552 AC: 2658 AN: 4814

European-Finnish (FIN) AF: 0.537 AC: 5676 AN: 10566

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41044 AN: 67996

Other (OTH) AF: 0.553 AC: 1171 AN: 2116

Alfa AF: 0.590 Hom.: 44096

Bravo AF: 0.557

Asia WGS AF: 0.610 AC: 2120 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	6.0
DANN	Benign	0.75
PhyloP100		0.35
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: rs516606; hg19: chr8-41595613;