10-27014676-A-T

Variant names:

• chr10-27014676-A-T
• rs2274741
• NM_014915.3:c.4542T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014915.3(ANKRD26):​c.4542T>A​(p.Phe1514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,612,226 control chromosomes in the GnomAD database, including 31,615 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3638 hom., cov: 32)
  • Exomes 𝑓: 0.17 (27977 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.718
• Publications: 21 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1472558E-4).
• BP6: Variant 10-27014676-A-T is Benign according to our data. Variant chr10-27014676-A-T is described in ClinVar as Benign. ClinVar VariationId is 260470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD26	NM_014915.3	c.4542T>A	p.Phe1514Leu	missense_variant	Exon 31 of 34	ENST00000376087.5	NP_055730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD26	ENST00000376087.5	c.4542T>A	p.Phe1514Leu	missense_variant	Exon 31 of 34	5	NM_014915.3	ENSP00000365255.4

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30341 AN: 151996 Hom.: 3620 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.221 AC: 54924 AN: 248202 AF XY: 0.225

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.552

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.173 AC: 252402 AN: 1460112 Hom.: 27977 Cov.: 32 AF XY: 0.178 AC XY: 128954 AN XY: 726344

African (AFR) AF: 0.222 AC: 7429 AN: 33420

American (AMR) AF: 0.182 AC: 8114 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5068 AN: 26104

East Asian (EAS) AF: 0.577 AC: 22838 AN: 39588

South Asian (SAS) AF: 0.344 AC: 29601 AN: 86168

European-Finnish (FIN) AF: 0.236 AC: 12581 AN: 53374

Middle Eastern (MID) AF: 0.191 AC: 1044 AN: 5470

European-Non Finnish (NFE) AF: 0.139 AC: 153963 AN: 1111056

Other (OTH) AF: 0.195 AC: 11764 AN: 60298

GnomAD4 genome AF: 0.200 AC: 30408 AN: 152114 Hom.: 3638 Cov.: 32 AF XY: 0.210 AC XY: 15621 AN XY: 74356

African (AFR) AF: 0.226 AC: 9369 AN: 41506

American (AMR) AF: 0.179 AC: 2727 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3470

East Asian (EAS) AF: 0.557 AC: 2885 AN: 5182

South Asian (SAS) AF: 0.368 AC: 1775 AN: 4820

European-Finnish (FIN) AF: 0.243 AC: 2567 AN: 10546

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9806 AN: 68004

Other (OTH) AF: 0.204 AC: 430 AN: 2108

Alfa AF: 0.164 Hom.: 1940

Bravo AF: 0.193

TwinsUK AF: 0.149 AC: 554

ALSPAC AF: 0.139 AC: 534

ESP6500AA AF: 0.233 AC: 841

ESP6500EA AF: 0.145 AC: 1181

ExAC AF: 0.222 AC: 26755

Asia WGS AF: 0.457 AC: 1585 AN: 3474

EpiCase AF: 0.148

EpiControl AF: 0.151

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 2 Benign:3

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.31
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.031	T;T
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		0.72
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.055
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.034
MPC		0.052
ClinPred		0.0047	T
GERP RS		1.3
PromoterAI		-0.0051	Neutral
Varity_R		0.041
gMVP		0.013
Mutation Taster		=100/0	polymorphism (auto)

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: rs2274741; hg19: chr10-27303605; COSMIC: COSV65774511;