chr8-41653891-C-T

Variant names:

• chr8-41653891-C-T
• rs72638943
• NM_000037.4:c.*1899G>A

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.*1899G>A 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 152,298 control chromosomes in the GnomAD database, including 220 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 (220 hom., cov: 33)
  • Exomes 𝑓: 0.042 (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: 1.13
• Publications: 3 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=-0.78).
• BP6: Variant 8-41653891-C-T is Benign according to our data. Variant chr8-41653891-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0826 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.*1899G>A		3_prime_UTR	Exon 43 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.*1836G>A		3_prime_UTR	Exon 43 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.*1836G>A		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.*1899G>A		3_prime_UTR	Exon 43 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.*1836G>A		3_prime_UTR	Exon 43 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.*1836G>A		3_prime_UTR	Exon 42 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0445 AC: 6777 AN: 152132 Hom.: 215 Cov.: 33

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00971

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0530

GnomAD4 exome AF: 0.0417 AC: 2 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.0526 AC XY: 2 AN XY: 38

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

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

European-Non Finnish (NFE) AF: 0.0238 AC: 1 AN: 42

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0447 AC: 6800 AN: 152250 Hom.: 220 Cov.: 33 AF XY: 0.0433 AC XY: 3221 AN XY: 74432

African (AFR) AF: 0.0849 AC: 3530 AN: 41562

American (AMR) AF: 0.0351 AC: 538 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.0310 AC: 150 AN: 4832

European-Finnish (FIN) AF: 0.00971 AC: 103 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0327 AC: 2223 AN: 68006

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

Alfa AF: 0.0401 Hom.: 18

Bravo AF: 0.0480

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	-0.78
CADD	Benign	8.6
DANN	Benign	0.84
PhyloP100		1.1
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: rs72638943; hg19: chr8-41511410;