8-41729232-T-C

Variant names:

• chr8-41729232-T-C
• rs7003385
• NM_000037.4:c.229-1226A>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.229-1226A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 151,972 control chromosomes in the GnomAD database, including 6,315 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 0.26 (6315 hom., cov: 33)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 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.229-1226A>G		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.328-1226A>G		intron	N/A	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.229-1226A>G		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.229-1226A>G		intron	N/A	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.328-1226A>G		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.229-1226A>G		intron	N/A	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40214 AN: 151854 Hom.: 6305 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.265 AC: 40247 AN: 151972 Hom.: 6315 Cov.: 33 AF XY: 0.264 AC XY: 19626 AN XY: 74260

African (AFR) AF: 0.116 AC: 4804 AN: 41434

American (AMR) AF: 0.300 AC: 4577 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3468

East Asian (EAS) AF: 0.0718 AC: 372 AN: 5184

South Asian (SAS) AF: 0.291 AC: 1403 AN: 4814

European-Finnish (FIN) AF: 0.400 AC: 4215 AN: 10528

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22831 AN: 67948

Other (OTH) AF: 0.272 AC: 576 AN: 2116

Alfa AF: 0.316 Hom.: 5700

Bravo AF: 0.250

Asia WGS AF: 0.242 AC: 842 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	0.35
DANN	Benign	0.48
PhyloP100		-0.11
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: rs7003385; hg19: chr8-41586750;