rs6987404

Variant names:

• chr8-41690794-C-T
• rs6987404
• NM_000037.4:c.3859-195G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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 -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 VariationId is 1273140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 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.3859-195G>A		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.3982-195G>A		intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.3859-195G>A		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.3859-195G>A		intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.3982-195G>A		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.3859-195G>A		intron	N/A	ENSP00000339620.4

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

African (AFR) AF: 0.475 AC: 19708 AN: 41492

American (AMR) AF: 0.0707 AC: 1082 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3472

East Asian (EAS) AF: 0.0688 AC: 357 AN: 5188

South Asian (SAS) AF: 0.0458 AC: 221 AN: 4824

European-Finnish (FIN) AF: 0.0297 AC: 315 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0546 AC: 3711 AN: 68024

Other (OTH) AF: 0.131 AC: 278 AN: 2116

Alfa AF: 0.0991 Hom.: 1423

Bravo AF: 0.188

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.3
DANN	Benign	0.50
PhyloP100		0.59
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: rs6987404; hg19: chr8-41548312;