rs34664882

Variant names:

• chr8-41686157-G-A
• rs34664882
• NM_000037.4:c.4385C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000037.4(ANK1):​c.4385C>T​(p.Ala1462Val) variant causes a missense change. The variant allele was found at a frequency of 0.0279 in 1,614,202 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1462T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (48 hom., cov: 33)
  • Exomes 𝑓: 0.029 (688 hom.)
• Consequence: ANK1 NM_000037.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.21
• Publications: 18 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 8-41686157-G-A is Benign according to our data. Variant chr8-41686157-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0204 (3115/152328) while in subpopulation NFE AF = 0.0286 (1947/68030). AF 95% confidence interval is 0.0276. There are 48 homozygotes in GnomAd4. There are 1416 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.4385C>T	p.Ala1462Val	missense	Exon 36 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.4508C>T	p.Ala1503Val	missense	Exon 37 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.4385C>T	p.Ala1462Val	missense	Exon 36 of 42	NP_065209.2	P16157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.4385C>T	p.Ala1462Val	missense	Exon 36 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.4508C>T	p.Ala1503Val	missense	Exon 37 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.4385C>T	p.Ala1462Val	missense	Exon 36 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3116 AN: 152210 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0227 AC: 5704 AN: 251492 AF XY: 0.0222

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0339

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: 0.0210

GnomAD4 exome AF: 0.0287 AC: 41963 AN: 1461874 Hom.: 688 Cov.: 32 AF XY: 0.0281 AC XY: 20471 AN XY: 727238

African (AFR) AF: 0.0141 AC: 473 AN: 33480

American (AMR) AF: 0.0313 AC: 1400 AN: 44724

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: 0.0163 AC: 872 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0322 AC: 35785 AN: 1111996

Other (OTH) AF: 0.0241 AC: 1454 AN: 60394

GnomAD4 genome AF: 0.0204 AC: 3115 AN: 152328 Hom.: 48 Cov.: 33 AF XY: 0.0190 AC XY: 1416 AN XY: 74488

African (AFR) AF: 0.0154 AC: 642 AN: 41572

American (AMR) AF: 0.0138 AC: 212 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4826

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0286 AC: 1947 AN: 68030

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0263 Hom.: 202

Bravo AF: 0.0209

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.0300 AC: 258

ExAC AF: 0.0219 AC: 2656

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0257

EpiControl AF: 0.0251

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0033	T
MetaSVM	Uncertain	-0.071	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.041	D
Sift4G	Benign	0.17	T
Polyphen		0.037	B
Vest4		0.12
MPC		0.30
ClinPred		0.031	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.63
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 2

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

Other links and lift over

dbSNP: rs34664882; hg19: chr8-41543675; COSMIC: COSV107218805;