rs77173848
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1
The ENST00000265709.14(ANK1):c.127-39509T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,532,402 control chromosomes in the GnomAD database, including 774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.044 ( 310 hom., cov: 32)
Exomes 𝑓: 0.021 ( 464 hom. )
Consequence
ANK1
ENST00000265709.14 intron
ENST00000265709.14 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.129
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 8-41797646-A-G is Benign according to our data. Variant chr8-41797646-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 507.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK1 | NM_000037.4 | upstream_gene_variant | ENST00000289734.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK1 | ENST00000265709.14 | c.127-39509T>C | intron_variant | 1 | P4 | ||||
ANK1 | ENST00000705521.1 | c.127-39509T>C | intron_variant | A2 | |||||
ANK1 | ENST00000289734.13 | upstream_gene_variant | 1 | NM_000037.4 | A2 | ||||
ANK1 | ENST00000347528.8 | upstream_gene_variant | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0436 AC: 6626AN: 152136Hom.: 307 Cov.: 32
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GnomAD4 exome AF: 0.0208 AC: 28684AN: 1380148Hom.: 464 Cov.: 27 AF XY: 0.0198 AC XY: 13508AN XY: 682036
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GnomAD4 genome ? AF: 0.0436 AC: 6645AN: 152254Hom.: 310 Cov.: 32 AF XY: 0.0421 AC XY: 3137AN XY: 74458
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Spherocytosis, type 1, autosomal recessive Benign:2
Benign, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_012820.1(NM_001142446.2):c.127-39509T>C in the ANK1 gene has an allele frequency of 0.112 in African subpopulation in the gnomAD database. 69 homozygous occurrences are observed in the gnomAD database. This variant was reported as -108T-C in a patient, compound heterozygous with V463I (PMID: 8640229). This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2, PM3. - |
Benign, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 19, 2023 | BA1, BS1, BP4 - |
not specified Benign:1
Benign, criteria provided, single submitter | research | H3Africa Consortium | Oct 28, 2020 | While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.123, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. - |
Hereditary spherocytosis type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at