rs61745662

Variant names:

• chr10-27035472-T-G
• rs61745662
• NM_014915.3:c.2978A>C

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.2978A>C​(p.Glu993Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00417 in 1,614,024 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E993K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (130 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.45
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002908945).
• BP6: Variant 10-27035472-T-G is Benign according to our data. Variant chr10-27035472-T-G is described in ClinVar as Benign. ClinVar VariationId is 260464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

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.2978A>C	p.Glu993Ala	missense	Exon 24 of 34	NP_055730.2	Q9UPS8-1
	ANKRD26	NM_001256053.2		c.2975A>C	p.Glu992Ala	missense	Exon 24 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.2978A>C	p.Glu993Ala	missense	Exon 24 of 34	ENSP00000365255.4	Q9UPS8-1
	ANKRD26	ENST00000436985.7	TSL:1	c.2975A>C	p.Glu992Ala	missense	Exon 24 of 34	ENSP00000405112.3	E7ESJ3
	ANKRD26	ENST00000968143.1		c.4064A>C	p.Glu1355Ala	missense	Exon 25 of 35	ENSP00000638202.1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3346 AN: 152130 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00555 AC: 1385 AN: 249442 AF XY: 0.00427

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00231 AC: 3382 AN: 1461776 Hom.: 130 Cov.: 32 AF XY: 0.00198 AC XY: 1437 AN XY: 727186

African (AFR) AF: 0.0838 AC: 2804 AN: 33476

American (AMR) AF: 0.00320 AC: 143 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111954

Other (OTH) AF: 0.00513 AC: 310 AN: 60392

GnomAD4 genome AF: 0.0220 AC: 3348 AN: 152248 Hom.: 133 Cov.: 32 AF XY: 0.0212 AC XY: 1579 AN XY: 74448

African (AFR) AF: 0.0767 AC: 3187 AN: 41544

American (AMR) AF: 0.00739 AC: 113 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67986

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00813 Hom.: 90

Bravo AF: 0.0254

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0741 AC: 279

ESP6500EA AF: 0.000607 AC: 5

ExAC AF: 0.00645 AC: 779

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Thrombocytopenia 2 (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.2	T
PhyloP100		6.4
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.18
Sift	Benign	0.051	T
Sift4G	Uncertain	0.017	D
Vest4		0.33
MVP		0.41
MPC		0.23
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.31
gMVP		0.088
Mutation Taster		=94/6	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: rs61745662; hg19: chr10-27324401;