rs1449107925

Variant names:

• chr10-27022648-A-C
• rs1449107925
• NM_014915.3:c.4125T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014915.3(ANKRD26):​c.4125T>G​(p.Asn1375Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1375S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.593
• Publications: 0 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, Ambry Genetics, G2P, 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11064461).

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.4125T>G	p.Asn1375Lys	missense	Exon 29 of 34	NP_055730.2
	ANKRD26	NM_001256053.2		c.4122T>G	p.Asn1374Lys	missense	Exon 29 of 34	NP_001242982.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.4125T>G	p.Asn1375Lys	missense	Exon 29 of 34	ENSP00000365255.4
	ANKRD26	ENST00000436985.7	TSL:1	c.4122T>G	p.Asn1374Lys	missense	Exon 29 of 34	ENSP00000405112.3
	ANKRD26	ENST00000968143.1		c.5211T>G	p.Asn1737Lys	missense	Exon 30 of 35	ENSP00000638202.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430894 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 711138

African (AFR) AF: 0.00 AC: 0 AN: 32872

American (AMR) AF: 0.00 AC: 0 AN: 43800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25222

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 85436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088822

Other (OTH) AF: 0.00 AC: 0 AN: 58740

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.32
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.59
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.085
Sift	Benign	0.28	T
Sift4G	Benign	0.89	T
Vest4		0.16
MVP		0.65
MPC		0.056
ClinPred		0.18	T
GERP RS		1.9
PromoterAI		-0.0036	Neutral
Varity_R		0.11
gMVP		0.076
Mutation Taster		=96/4	polymorphism

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: rs1449107925; hg19: chr10-27311577;