rs34265667

Variant names:

• chr8-41684575-G-A
• rs34265667
• NM_000037.4:c.4506C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000037.4(ANK1):​c.4506C>T​(p.Arg1502Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,613,766 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 33)
  • Exomes 𝑓: 0.029 (688 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.368
• Publications: 10 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: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-41684575-G-A is Benign according to our data. Variant chr8-41684575-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.368 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3116/152338) while in subpopulation NFE AF = 0.0286 (1948/68038). AF 95% confidence interval is 0.0276. There are 49 homozygotes in GnomAd4. There are 1415 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.4506C>T	p.Arg1502Arg	synonymous	Exon 37 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.4629C>T	p.Arg1543Arg	synonymous	Exon 38 of 43	NP_001135918.1
	ANK1	NM_020476.3		c.4506C>T	p.Arg1502Arg	synonymous	Exon 37 of 42	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.4506C>T	p.Arg1502Arg	synonymous	Exon 37 of 43	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.4629C>T	p.Arg1543Arg	synonymous	Exon 38 of 43	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.4506C>T	p.Arg1502Arg	synonymous	Exon 37 of 42	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3117 AN: 152222 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0227 AC: 5697 AN: 250946 AF XY: 0.0222

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0287 AC: 41989 AN: 1461428 Hom.: 688 Cov.: 32 AF XY: 0.0282 AC XY: 20479 AN XY: 727028

African (AFR) AF: 0.0141 AC: 473 AN: 33476

American (AMR) AF: 0.0315 AC: 1408 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0157 AC: 1358 AN: 86258

European-Finnish (FIN) AF: 0.0164 AC: 867 AN: 52992

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.0322 AC: 35805 AN: 1111992

Other (OTH) AF: 0.0241 AC: 1457 AN: 60386

GnomAD4 genome AF: 0.0205 AC: 3116 AN: 152338 Hom.: 49 Cov.: 33 AF XY: 0.0190 AC XY: 1415 AN XY: 74492

African (AFR) AF: 0.0153 AC: 637 AN: 41582

American (AMR) AF: 0.0140 AC: 214 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4834

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0286 AC: 1948 AN: 68038

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0262 Hom.: 191

Bravo AF: 0.0209

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0258

EpiControl AF: 0.0251

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spherocytosis type 1 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.1
DANN	Benign	0.64
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34265667; hg19: chr8-41542093;