chr8-41715748-G-A

Variant names:

• chr8-41715748-G-A
• rs34387324
• NM_000037.4:c.1506C>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.1506C>T​(p.Ala502Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,614,234 control chromosomes in the GnomAD database, including 47 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 0.0039 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (41 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -4.47
• Publications: 2 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=-0.7).
• BP6: Variant 8-41715748-G-A is Benign according to our data. Variant chr8-41715748-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261291.
• BP7: Synonymous conserved (PhyloP=-4.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00392 (597/152368) while in subpopulation NFE AF = 0.00654 (445/68036). AF 95% confidence interval is 0.00604. There are 6 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1506C>T	p.Ala502Ala	synonymous	Exon 14 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.1605C>T	p.Ala535Ala	synonymous	Exon 14 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.1506C>T	p.Ala502Ala	synonymous	Exon 14 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.1506C>T	p.Ala502Ala	synonymous	Exon 14 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.1605C>T	p.Ala535Ala	synonymous	Exon 14 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.1506C>T	p.Ala502Ala	synonymous	Exon 14 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152250 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00654

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00391 AC: 982 AN: 251462 AF XY: 0.00399

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00640 AC: 9351 AN: 1461866 Hom.: 41 Cov.: 32 AF XY: 0.00623 AC XY: 4534 AN XY: 727234

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86256

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53410

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00789 AC: 8769 AN: 1112012

Other (OTH) AF: 0.00503 AC: 304 AN: 60396

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152368 Hom.: 6 Cov.: 33 AF XY: 0.00366 AC XY: 273 AN XY: 74510

African (AFR) AF: 0.00113 AC: 47 AN: 41586

American (AMR) AF: 0.00503 AC: 77 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00654 AC: 445 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00544 Hom.: 2

Bravo AF: 0.00385

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00640

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	-0.70
CADD	Benign	1.1
DANN	Benign	0.84
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	polymorphism

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: rs34387324; hg19: chr8-41573266;