rs10093583

Variant names:

• chr8-41690485-T-C
• rs10093583
• NM_000037.4:c.3973A>G
• ANK1 p.Met1325Val

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000037.4(ANK1):​c.3973A>G​(p.Met1325Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,144 control chromosomes in the GnomAD database, including 607 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (285 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (322 hom.)
• Consequence: ANK1 NM_000037.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.98
• Publications: 15 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: AD, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• hereditary spherocytosis type 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012792349).
• BP6: Variant 8-41690485-T-C is Benign according to our data. Variant chr8-41690485-T-C is described in ClinVar as Benign. ClinVar VariationId is 261307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 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.3973A>G	p.Met1325Val	missense	Exon 32 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.4096A>G	p.Met1366Val	missense	Exon 33 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.3973A>G	p.Met1325Val	missense	Exon 32 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.3973A>G	p.Met1325Val	missense	Exon 32 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.4096A>G	p.Met1366Val	missense	Exon 33 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.3973A>G	p.Met1325Val	missense	Exon 32 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5777 AN: 152156 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0135 AC: 3392 AN: 251442 AF XY: 0.0111

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00935 AC: 13669 AN: 1461870 Hom.: 322 Cov.: 33 AF XY: 0.00889 AC XY: 6468 AN XY: 727238

African (AFR) AF: 0.123 AC: 4112 AN: 33480

American (AMR) AF: 0.0107 AC: 477 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 372 AN: 26136

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

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86258

European-Finnish (FIN) AF: 0.00577 AC: 308 AN: 53410

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00658 AC: 7316 AN: 1111998

Other (OTH) AF: 0.0145 AC: 876 AN: 60396

GnomAD4 genome AF: 0.0380 AC: 5784 AN: 152274 Hom.: 285 Cov.: 33 AF XY: 0.0369 AC XY: 2747 AN XY: 74462

African (AFR) AF: 0.118 AC: 4902 AN: 41534

American (AMR) AF: 0.0174 AC: 267 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00489 AC: 52 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00631 AC: 429 AN: 68012

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0191 Hom.: 358

Bravo AF: 0.0434

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00693

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.054
Sift	Benign	0.12	T
Sift4G	Benign	0.27	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.23
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10093583;

hg19: chr8-41548003;

COSMIC: COSV107217324;

COSMIC: COSV107217324;