chr10-27100460-C-T

Variant names:

• chr10-27100460-C-T
• rs863223318
• NM_014915.3:c.-134G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV007096875: Mutagenesis studies showed this variant interferes with protein expression and affects megakaryopoiesis and platelet production (PMID:21211618)" and additional evidence is available in ClinVar.

• 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:9
• Conservation: PhyloP100: -0.969
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• thrombocytopenia 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV007096875: Mutagenesis studies showed this variant interferes with protein expression and affects megakaryopoiesis and platelet production (PMID:21211618); SCV003441416: Studies have shown that this variant alters ANKRD26 gene expression (PMID: 21211618).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 30853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	NM_014915.3	MANE Select	c.-134G>A		5_prime_UTR	Exon 1 of 34	NP_055730.2	Q9UPS8-1
	ANKRD26	NM_001256053.2		c.-134G>A		5_prime_UTR	Exon 1 of 34	NP_001242982.1	E7ESJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.-134G>A		5_prime_UTR	Exon 1 of 34	ENSP00000365255.4	Q9UPS8-1
	ANKRD26	ENST00000436985.7	TSL:1	c.-134G>A		5_prime_UTR	Exon 1 of 34	ENSP00000405112.3	E7ESJ3
	ANKRD26	ENST00000968143.1		c.-134G>A		5_prime_UTR	Exon 1 of 35	ENSP00000638202.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Thrombocytopenia 2 (4)
3	-	-	not provided (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.89
PhyloP100		-0.97
PromoterAI		0.86	Over-expression
Mutation Taster		=77/223	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863223318; hg19: chr10-27389389;