8-41710353-C-T

Variant names:

• chr8-41710353-C-T
• rs10504043
• NM_000037.4:c.1801-1378G>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.1801-1378G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 152,264 control chromosomes in the GnomAD database, including 188 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 0.037 (188 hom., cov: 33)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.768
• 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: 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0911 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.1801-1378G>A		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.1900-1378G>A		intron	N/A	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.1801-1378G>A		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.1801-1378G>A		intron	N/A	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.1900-1378G>A		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.1801-1378G>A		intron	N/A	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5607 AN: 152146 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0263

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

GnomAD4 genome AF: 0.0369 AC: 5616 AN: 152264 Hom.: 188 Cov.: 33 AF XY: 0.0357 AC XY: 2659 AN XY: 74462

African (AFR) AF: 0.0935 AC: 3883 AN: 41522

American (AMR) AF: 0.0157 AC: 240 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

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

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4820

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0147 AC: 999 AN: 68028

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0205 Hom.: 27

Bravo AF: 0.0379

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.86
DANN	Benign	0.43
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism

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: rs10504043; hg19: chr8-41567871;