rs7816734

Positions:

• chr8-41690230-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.4101C>T​(p.Ala1367=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,614,014 control chromosomes in the GnomAD database, including 11,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4902 hom., cov: 33)
  • Exomes 𝑓: 0.066 (6503 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.74

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 8-41690230-G-A is Benign according to our data. Variant chr8-41690230-G-A is described in ClinVar as [Benign]. Clinvar id is 261309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41690230-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.4101C>T	p.Ala1367=	synonymous_variant	33/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.4101C>T	p.Ala1367=	synonymous_variant	33/43	1	NM_000037.4	ENSP00000289734	A2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25888 AN: 152084 Hom.: 4888 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.0797 AC: 20028 AN: 251330 Hom.: 2288 AF XY: 0.0717 AC XY: 9736 AN XY: 135880

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0723

Gnomad SAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0661 AC: 96602 AN: 1461812 Hom.: 6503 Cov.: 33 AF XY: 0.0640 AC XY: 46563 AN XY: 727190

Gnomad4 AFR exome AF: 0.483

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.0740

Gnomad4 SAS exome AF: 0.0452

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0565

Gnomad4 OTH exome AF: 0.0802

GnomAD4 genome AF: 0.171 AC: 25955 AN: 152202 Hom.: 4902 Cov.: 33 AF XY: 0.163 AC XY: 12157 AN XY: 74418

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.0705

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.0693

Gnomad4 SAS AF: 0.0458

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0544

Gnomad4 OTH AF: 0.131

Alfa AF: 0.101 Hom.: 1394

Bravo AF: 0.188

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0528

EpiControl AF: 0.0503

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Spherocytosis 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7816734; hg19: chr8-41547748;