chr8-41654181-G-C

Position:

• chr8-41654181-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000037.4(ANK1):​c.*1609C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 152,752 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (218 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: ANK1 NM_000037.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.921

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-41654181-G-C is Benign according to our data. Variant chr8-41654181-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 362961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.*1609C>G		3_prime_UTR_variant	43/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.*1609C>G		3_prime_UTR_variant	43/43	1	NM_000037.4	A2
ANK1	ENST00000265709.14	c.*1546C>G		3_prime_UTR_variant	43/43	1		P4
ANK1	ENST00000347528.8	c.*1546C>G		3_prime_UTR_variant	42/42	1		A2
ANK1	ENST00000522543.6	c.*1546C>G		3_prime_UTR_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6802 AN: 152116 Hom.: 213 Cov.: 33

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0530

GnomAD4 exome AF: 0.0135 AC: 7 AN: 518 Hom.: 0 Cov.: 0 AF XY: 0.0183 AC XY: 6 AN XY: 328

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0448 AC: 6825 AN: 152234 Hom.: 218 Cov.: 33 AF XY: 0.0434 AC XY: 3229 AN XY: 74440

Gnomad4 AFR AF: 0.0851

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0312

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.0329

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0389 Hom.: 17

Bravo AF: 0.0483

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spherocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.9
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78203311; hg19: chr8-41511700;