8-41729232-T-C

Position:

• chr8-41729232-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.229-1226A>G		intron_variant		ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.229-1226A>G		intron_variant		1	NM_000037.4	ENSP00000289734	A2

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

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.0718

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.272

Alfa AF: 0.319 Hom.: 4302

Bravo AF: 0.250

Asia WGS AF: 0.242 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs7003385; hg19: chr8-41586750;