8-41672476-G-A

Variant names:

• chr8-41672476-G-A
• rs149859024
• NM_000037.4:c.4974C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000037.4(ANK1):​c.4974C>T​(p.Asp1658Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,614,196 control chromosomes in the GnomAD database, including 45 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 0.0043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (44 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.59
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 8-41672476-G-A is Benign according to our data. Variant chr8-41672476-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261314.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00435 (662/152302) while in subpopulation NFE AF = 0.00741 (504/68018). AF 95% confidence interval is 0.00688. There are 1 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 44 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.4974C>T	p.Asp1658Asp	synonymous	Exon 38 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.5097C>T	p.Asp1699Asp	synonymous	Exon 39 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.4974C>T	p.Asp1658Asp	synonymous	Exon 38 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.4974C>T	p.Asp1658Asp	synonymous	Exon 38 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.5097C>T	p.Asp1699Asp	synonymous	Exon 39 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.4974C>T	p.Asp1658Asp	synonymous	Exon 38 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 662 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00741

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00405 AC: 1019 AN: 251492 AF XY: 0.00391

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00651

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00700 AC: 10227 AN: 1461894 Hom.: 44 Cov.: 38 AF XY: 0.00682 AC XY: 4961 AN XY: 727248

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26136

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

South Asian (SAS) AF: 0.00152 AC: 131 AN: 86258

European-Finnish (FIN) AF: 0.00288 AC: 154 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00837 AC: 9312 AN: 1112012

Other (OTH) AF: 0.00651 AC: 393 AN: 60396

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00395 AC XY: 294 AN XY: 74472

African (AFR) AF: 0.00118 AC: 49 AN: 41566

American (AMR) AF: 0.00274 AC: 42 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00741 AC: 504 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00385 Hom.: 3

Bravo AF: 0.00403

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spherocytosis type 1 (2)
-	-	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	-0.63
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149859024; hg19: chr8-41529994; COSMIC: COSV55885635;