8-41654181-G-C

Variant names:

• chr8-41654181-G-C
• rs78203311
• NM_000037.4:c.*1609C>G

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.*1609C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 152,752 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (218 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: ANK1 NM_000037.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.921
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-41654181-G-C is Benign according to our data. Variant chr8-41654181-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0828 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.*1609C>G		3_prime_UTR	Exon 43 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.*1546C>G		3_prime_UTR	Exon 43 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.*1546C>G		3_prime_UTR	Exon 42 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.*1609C>G		3_prime_UTR	Exon 43 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.*1546C>G		3_prime_UTR	Exon 43 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.*1546C>G		3_prime_UTR	Exon 42 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6802 AN: 152116 Hom.: 213 Cov.: 33

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0530

GnomAD4 exome AF: 0.0135 AC: 7 AN: 518 Hom.: 0 Cov.: 0 AF XY: 0.0183 AC XY: 6 AN XY: 328

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0117 AC: 5 AN: 428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0256 AC: 2 AN: 78

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.0448 AC: 6825 AN: 152234 Hom.: 218 Cov.: 33 AF XY: 0.0434 AC XY: 3229 AN XY: 74440

African (AFR) AF: 0.0851 AC: 3536 AN: 41554

American (AMR) AF: 0.0352 AC: 539 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.0312 AC: 151 AN: 4834

European-Finnish (FIN) AF: 0.00989 AC: 105 AN: 10622

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0329 AC: 2238 AN: 67976

Other (OTH) AF: 0.0520 AC: 110 AN: 2116

Alfa AF: 0.0389 Hom.: 17

Bravo AF: 0.0483

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.9
DANN	Benign	0.72
PhyloP100		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs78203311; hg19: chr8-41511700;