rs863223318

Positions:

• chr10-27100460-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_014915.3(ANKRD26):​c.-134G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ANKRD26 NM_014915.3 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.969

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-27100460-C-T is Pathogenic according to our data. Variant chr10-27100460-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-27100460-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD26	NM_014915.3	c.-134G>A		5_prime_UTR_variant	1/34	ENST00000376087.5	NP_055730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD26	ENST00000376087.5	c.-134G>A		5_prime_UTR_variant	1/34	5	NM_014915.3	ENSP00000365255.4
ANKRD26	ENST00000436985.7	c.-134G>A		5_prime_UTR_variant	1/34	1		ENSP00000405112.3
ANKRD26	ENST00000676420.1	n.-134G>A		non_coding_transcript_exon_variant	1/25			ENSP00000502355.1
ANKRD26	ENST00000676420.1	n.-134G>A		5_prime_UTR_variant	1/25			ENSP00000502355.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 02, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 07, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This variant occurs in a non-coding region of the ANKRD26 gene. It does not change the encoded amino acid sequence of the ANKRD26 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial thrombocytopenia (PMID: 21211618, 26175287, 26884589, 28277066, 31064749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30853). Studies have shown that this variant alters ANKRD26 gene expression (PMID: 21211618). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 05, 2024	PP1_strong, PM1, PM2_moderate, PS3_moderate, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ANKRD26: PP1:Strong, PM1, PM2, PS4:Moderate, PP4, PS3:Supporting -

Thrombocytopenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223318; hg19: chr10-27389389;