rs7816734

Variant names:

• chr8-41690230-G-A
• rs7816734
• NM_000037.4:c.4101C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.4101C>T​(p.Ala1367Ala) 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
• 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: 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 -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 VariationId is 261309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.4101C>T	p.Ala1367Ala	synonymous	Exon 33 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.4224C>T	p.Ala1408Ala	synonymous	Exon 34 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.4101C>T	p.Ala1367Ala	synonymous	Exon 33 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.4101C>T	p.Ala1367Ala	synonymous	Exon 33 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.4224C>T	p.Ala1408Ala	synonymous	Exon 34 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.4101C>T	p.Ala1367Ala	synonymous	Exon 33 of 42	ENSP00000339620.4	P16157-1

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

GnomAD2 exomes AF: 0.0797 AC: 20028 AN: 251330 AF XY: 0.0717

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 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

African (AFR) AF: 0.483 AC: 16161 AN: 33476

American (AMR) AF: 0.0463 AC: 2070 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1754 AN: 26136

East Asian (EAS) AF: 0.0740 AC: 2939 AN: 39700

South Asian (SAS) AF: 0.0452 AC: 3895 AN: 86256

European-Finnish (FIN) AF: 0.0340 AC: 1815 AN: 53408

Middle Eastern (MID) AF: 0.0560 AC: 320 AN: 5716

European-Non Finnish (NFE) AF: 0.0565 AC: 62807 AN: 1112006

Other (OTH) AF: 0.0802 AC: 4841 AN: 60392

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

African (AFR) AF: 0.475 AC: 19685 AN: 41476

American (AMR) AF: 0.0705 AC: 1077 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3472

East Asian (EAS) AF: 0.0693 AC: 358 AN: 5166

South Asian (SAS) AF: 0.0458 AC: 221 AN: 4830

European-Finnish (FIN) AF: 0.0296 AC: 315 AN: 10624

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0544 AC: 3698 AN: 68028

Other (OTH) AF: 0.131 AC: 277 AN: 2114

Alfa AF: 0.105 Hom.: 1607

Bravo AF: 0.188

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0528

EpiControl AF: 0.0503

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7816734; hg19: chr8-41547748;