rs886046949
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
Consequence
NM_014915.3 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANKRD26 | ENST00000376087.5 | c.-113A>C | 5_prime_UTR_variant | Exon 1 of 34 | 5 | NM_014915.3 | ENSP00000365255.4 | |||
ANKRD26 | ENST00000436985.7 | c.-113A>C | 5_prime_UTR_variant | Exon 1 of 34 | 1 | ENSP00000405112.3 | ||||
ANKRD26 | ENST00000676420.1 | n.-113A>C | non_coding_transcript_exon_variant | Exon 1 of 25 | ENSP00000502355.1 | |||||
ANKRD26 | ENST00000676420.1 | n.-113A>C | 5_prime_UTR_variant | Exon 1 of 25 | ENSP00000502355.1 |
Frequencies
GnomAD3 genomes AF: 0.000381 AC: 58AN: 152162Hom.: 1 Cov.: 34
GnomAD4 exome AF: 0.000292 AC: 384AN: 1314172Hom.: 2 Cov.: 21 AF XY: 0.000282 AC XY: 184AN XY: 651692
GnomAD4 genome AF: 0.000381 AC: 58AN: 152280Hom.: 1 Cov.: 34 AF XY: 0.000403 AC XY: 30AN XY: 74454
ClinVar
Submissions by phenotype
not specified Uncertain:2
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. -
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not provided Uncertain:2
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. -
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at