rs77173848

chr8-41797646-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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]

ACMG classification

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: 6626 AN: 152136 Hom.: 307 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0253

GnomAD4 exome AF: 0.0208 AC: 28684 AN: 1380148 Hom.: 464 Cov.: 27 AF XY: 0.0198 AC XY: 13508 AN XY: 682036

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.0281

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.00348

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0436 AC: 6645 AN: 152254 Hom.: 310 Cov.: 32 AF XY: 0.0421 AC XY: 3137 AN XY: 74458

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0329 Hom.: 24

Bravo AF: 0.0480

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.10
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77173848; hg19: chr8-41655164; COSMIC: COSV55880044; COSMIC: COSV55880044;