8-41708992-C-T

Variant names:

• chr8-41708992-C-T
• rs786205243
• NM_000037.4:c.1801-17G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_000037.4(ANK1):​c.1801-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004563382: in-vitro functional assays suggest altered splicing by creating a novel cryptic acceptor splice site. REFERENCES Duru F et al. Homozygosity for dominant form of hereditary spherocytosis. Br J Haematol. 1992 Nov. PMID:1486040 Edelman EJ et al. A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis. Blood. 2007 Jun 15. PMID:17327413 Kang LL et al. Gilbert's syndrome coexisting with hereditary spherocytosis might not be rare: Six case reports. World J Clin Cases. 2020 May 26. PMID:32518793" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANK1 NM_000037.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -1.04
• Publications: 3 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004563382: in-vitro functional assays suggest altered splicing by creating a novel cryptic acceptor splice site. REFERENCES Duru F et al. Homozygosity for dominant form of hereditary spherocytosis. Br J Haematol. 1992 Nov. PMID: 1486040 Edelman EJ et al. A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis. Blood. 2007 Jun 15. PMID: 17327413 Kang LL et al. Gilbert's syndrome coexisting with hereditary spherocytosis might not be rare: Six case reports. World J Clin Cases. 2020 May 26. PMID: 32518793; SCV005835376: Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 17327413).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-41708992-C-T is Pathogenic according to our data. Variant chr8-41708992-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1801-17G>A		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.1900-17G>A		intron	N/A	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.1801-17G>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.1801-17G>A		intron	N/A	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.1900-17G>A		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.1801-17G>A		intron	N/A	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461066 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spherocytosis type 1 (3)
3	-	-	not provided (3)
1	-	-	SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	18
DANN	Benign	0.69
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205243; hg19: chr8-41566510;