rs75445709

Variant names:

• chr10-27038058-C-T
• rs75445709
• NM_014915.3:c.2376-4G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014915.3(ANKRD26):​c.2376-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,605,426 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (117 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (108 hom.)
• Consequence: ANKRD26 NM_014915.3 splice_region, intron
• Scores: Splicing: ADA: 0.001268
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.566
• Publications: 1 publications found

Genes affected

ANKRD26 (HGNC:29186): (ankyrin repeat domain containing 26) This gene encodes a protein containing N-terminal ankyrin repeats which function in protein-protein interactions. Mutations in this gene are associated with autosomal dominant thrombocytopenia-2. Pseudogenes of this gene are found on chromosome 7, 10, 13 and 16. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ANKRD26 Gene-Disease associations (from GenCC):

• thrombocytopenia 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-27038058-C-T is Benign according to our data. Variant chr10-27038058-C-T is described in ClinVar as Benign. ClinVar VariationId is 260462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	NM_014915.3	MANE Select	c.2376-4G>A		splice_region intron	N/A	NP_055730.2
	ANKRD26	NM_001256053.2		c.2373-4G>A		splice_region intron	N/A	NP_001242982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.2376-4G>A		splice_region intron	N/A	ENSP00000365255.4
	ANKRD26	ENST00000436985.7	TSL:1	c.2373-4G>A		splice_region intron	N/A	ENSP00000405112.3
	ANKRD26	ENST00000490015.1	TSL:3	n.574-4G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3172 AN: 152044 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00537 AC: 1314 AN: 244792 AF XY: 0.00417

Gnomad AFR exome AF: 0.0761

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00216 AC: 3140 AN: 1453264 Hom.: 108 Cov.: 30 AF XY: 0.00188 AC XY: 1361 AN XY: 723296

African (AFR) AF: 0.0778 AC: 2589 AN: 33280

American (AMR) AF: 0.00314 AC: 140 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39516

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48708

Middle Eastern (MID) AF: 0.00369 AC: 21 AN: 5688

European-Non Finnish (NFE) AF: 0.0000721 AC: 80 AN: 1109110

Other (OTH) AF: 0.00473 AC: 285 AN: 60218

GnomAD4 genome AF: 0.0209 AC: 3174 AN: 152162 Hom.: 117 Cov.: 32 AF XY: 0.0200 AC XY: 1485 AN XY: 74402

African (AFR) AF: 0.0727 AC: 3017 AN: 41488

American (AMR) AF: 0.00706 AC: 108 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68014

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00751 Hom.: 12

Bravo AF: 0.0240

Asia WGS AF: 0.00145 AC: 5 AN: 3470

EpiCase AF: 0.000109

EpiControl AF: 0.000298

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Thrombocytopenia 2 (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.8
DANN	Benign	0.58
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.046
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: rs75445709; hg19: chr10-27326987;