rs6987404

Positions:

• chr8-41690794-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000037.4(ANK1):​c.3859-195G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,230 control chromosomes in the GnomAD database, including 4,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.17 (4909 hom., cov: 33)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.586

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-41690794-C-T is Benign according to our data. Variant chr8-41690794-C-T is described in ClinVar as [Benign]. Clinvar id is 1273140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41690794-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.3859-195G>A		intron_variant		ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.3859-195G>A		intron_variant		1	NM_000037.4	ENSP00000289734	A2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25929 AN: 152112 Hom.: 4895 Cov.: 33

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.0687

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.171 AC: 25996 AN: 152230 Hom.: 4909 Cov.: 33 AF XY: 0.164 AC XY: 12179 AN XY: 74424

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.0707

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.0688

Gnomad4 SAS AF: 0.0458

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0947 Hom.: 935

Bravo AF: 0.188

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.3
DANN	Benign	0.50

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: rs6987404; hg19: chr8-41548312;