rs1554800065

Positions:

• chr10-27100445-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014915.3(ANKRD26):​c.-119C>G 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ANKRD26 NM_014915.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 0.553

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD26	NM_014915.3	c.-119C>G		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.-119C>G		5_prime_UTR_variant	1/34	5	NM_014915.3	ENSP00000365255	A2
ANKRD26	ENST00000436985.7	c.-119C>G		5_prime_UTR_variant	1/34	1		ENSP00000405112	P4
ANKRD26	ENST00000676420.1	c.-119C>G		5_prime_UTR_variant, NMD_transcript_variant	1/25			ENSP00000502355

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	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 ANKRD26-related conditions (PMID: 28104920, 28669401, 32581362). ClinVar contains an entry for this variant (Variation ID: 434210). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2019	No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 28669401, 28104920, 32581362) -

Thrombocytopenia 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 02, 2015

- -

Thrombocytopenia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 29, 2023

Variant summary: ANKRD26 c.-119C>G is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 31370 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-119C>G has been reported in the literature in an individual who underwent Myelodysplastic syndrome (MDS) and acute leukemia (AL) panel testing (example: Guidugli_2017) and authors classified the variant as pathogenic or likely pathogenic. However, this report does not provide unequivocal conclusions about association of the variant with Thrombocytopenia 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28669401, 28104920, 32581362). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1554800065; hg19: chr10-27389374;