10-27053384-T-G

Variant names:

• chr10-27053384-T-G
• rs199656285
• NM_014915.3:c.1571A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014915.3(ANKRD26):​c.1571A>C​(p.His524Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H524R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029448688).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	NM_014915.3	MANE Select	c.1571A>C	p.His524Pro	missense	Exon 16 of 34	NP_055730.2
	ANKRD26	NM_001256053.2		c.1571A>C	p.His524Pro	missense	Exon 16 of 34	NP_001242982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.1571A>C	p.His524Pro	missense	Exon 16 of 34	ENSP00000365255.4
	ANKRD26	ENST00000436985.7	TSL:1	c.1571A>C	p.His524Pro	missense	Exon 16 of 34	ENSP00000405112.3
	ANKRD26	ENST00000675187.1		n.*910A>C		non_coding_transcript_exon	Exon 13 of 18	ENSP00000502611.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458012 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725386

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109976

Other (OTH) AF: 0.00 AC: 0 AN: 60240

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.4
DANN	Benign	0.16
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		0.18
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.021
Sift	Benign	0.30	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.20		Gain of relative solvent accessibility (P = 0.005)
MVP		0.088
MPC		0.066
ClinPred		0.18	T
GERP RS		-7.3
Varity_R		0.052
gMVP		0.013
Mutation Taster		=98/2	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: rs199656285; hg19: chr10-27342313;