Variant rs886046949 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.406

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ANKRD26	NM_014915.3 link	c.-113A>C		5_prime_UTR_variant	Exon 1 of 34	ENST00000376087.5	NP_055730.2	Q9UPS8-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKRD26	ENST00000376087.5 link	c.-113A>C	5_prime_UTR_variant	Exon 1 of 34	5	NM_014915.3	ENSP00000365255.4	Q9UPS8-1
ANKRD26	ENST00000436985.7 link	c.-113A>C	5_prime_UTR_variant	Exon 1 of 34	1		ENSP00000405112.3	E7ESJ3
ANKRD26	ENST00000676420.1 link	n.-113A>C	non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000502355.1	A0A6Q8PGU7
ANKRD26	ENST00000676420.1 link	n.-113A>C	5_prime_UTR_variant	Exon 1 of 25			ENSP00000502355.1	A0A6Q8PGU7

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000282

AC XY:

184

AN XY:

651692

show subpopulations

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:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74454

show subpopulations

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.:

Bravo

AF:

0.000438

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2025	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, hemizygous or homoplasmic 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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over