rs372696694

Variant names:

• chr8-41727998-G-A
• rs372696694
• NM_000037.4:c.237C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000037.4(ANK1):​c.237C>T​(p.Asn79Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00126 in 1,614,022 control chromosomes in the GnomAD database, including 30 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 0.00080 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.84
• 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: AD, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hereditary spherocytosis type 1

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-41727998-G-A is Benign according to our data. Variant chr8-41727998-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261300.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000801 (122/152298) while in subpopulation SAS AF = 0.0251 (121/4824). AF 95% confidence interval is 0.0215. There are 4 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.237C>T	p.Asn79Asn	synonymous	Exon 4 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.336C>T	p.Asn112Asn	synonymous	Exon 4 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.237C>T	p.Asn79Asn	synonymous	Exon 4 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.237C>T	p.Asn79Asn	synonymous	Exon 4 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.336C>T	p.Asn112Asn	synonymous	Exon 4 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.237C>T	p.Asn79Asn	synonymous	Exon 4 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152180 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00266 AC: 669 AN: 251212 AF XY: 0.00348

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00131 AC: 1911 AN: 1461724 Hom.: 26 Cov.: 36 AF XY: 0.00184 AC XY: 1336 AN XY: 727178

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0208 AC: 1792 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112008

Other (OTH) AF: 0.00156 AC: 94 AN: 60394

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152298 Hom.: 4 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000151

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.3
DANN	Benign	0.62
PhyloP100		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=66/34	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: rs372696694; hg19: chr8-41585516;