rs886046949

Positions:

• chr10-27100439-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_014915.3(ANKRD26):​c.-113A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,466,452 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: ANKRD26 NM_014915.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.406

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000381 (58/152280) while in subpopulation AMR AF= 0.00209 (32/15308). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD26	NM_014915.3	c.-113A>C		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.-113A>C		5_prime_UTR_variant	1/34	5	NM_014915.3	ENSP00000365255	A2
ANKRD26	ENST00000436985.7	c.-113A>C		5_prime_UTR_variant	1/34	1		ENSP00000405112	P4
ANKRD26	ENST00000676420.1	c.-113A>C		5_prime_UTR_variant, NMD_transcript_variant	1/25			ENSP00000502355

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152162 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000292 AC: 384 AN: 1314172 Hom.: 2 Cov.: 21 AF XY: 0.000282 AC XY: 184 AN XY: 651692

Gnomad4 AFR exome AF: 0.0000338

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152280 Hom.: 1 Cov.: 34 AF XY: 0.000403 AC XY: 30 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000438

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 15, 2020	DNA sequence analysis of the ANKRD26 gene demonstrated a sequence change in the 5 prime untranslated region (5'UTR), c.-113A>C. This sequence change has been described in the gnomAD database with a low population frequency of 0.019% (dbSNP rs886046949). The c.-113A>C change has been described in a patient with thrombocytopenia (PMID: 21467542). This sequence change occurs in a region where other pathogenic sequence changes have been reported in patients with ANKRD26-related thrombocytopenia. The functional significance of this sequence change is not known at present and its contribution to a disease phenotype cannot definitively be determined. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 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 present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individual(s) with thrombocytopenia 2 (PMID: 21467542). It has also been observed to segregate with disease in related individuals. This variant has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 28669401). ClinVar contains an entry for this variant (Variation ID: 299768). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 27, 2024	Observed in individuals with thrombocytopenia but also in unaffected controls (PMID: 21467542, 28669401); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; This variant is associated with the following publications: (PMID: 28277066, 24430186, 21467542, 32351539, 31275945, 28669401, 35751752, Kuzmanovic2022[abstract], 35587581) -

ANKRD26-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

The ANKRD26 c.-113A>C variant is located in the 5' untranslated region. This variant has been reported in three individuals from the same family with thrombocytopenia (Noris et al. 2011. PubMed ID: 21467542). This variant has also been reported in a large screen of individuals with rare diseases that found the variant in multiple individuals who did not display bleeding/platelet phenotypes (Greene et al. 2017. PubMed ID: 28669401). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a fully-penetrant pathogenic variant. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/299768/). At this time, the clinical significance of this variant is uncertain due to the conflicting evidence. -

Thrombocytopenia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

Noris et al. (2001) identified the c.-113A>C variant in the 5' untranslated region of the ANKRD26 gene in an Italian patient with thrombocytopenia 2. Available relatives of this patient were tested and the variant was detected in two other affected individuals. Control data are unavailable for this variant which it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The evidence for this variant is limited. The c.-113A>C variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for thrombocytopenia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.6
DANN	Benign	0.80
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: rs886046949; hg19: chr10-27389368;