NM_014915.3:c.-113A>C

Variant names:

• chr10-27100439-T-G
• rs886046949
• NM_014915.3:c.-113A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_014915.3(ANKRD26):​c.-113A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,466,452 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: ANKRD26 NM_014915.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.406
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152280) while in subpopulation AMR AF = 0.00209 (32/15308). AF 95% confidence interval is 0.00152. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 58 AD gene.

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.-113A>C		5_prime_UTR	Exon 1 of 34	NP_055730.2	Q9UPS8-1
	ANKRD26	NM_001256053.2		c.-113A>C		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.-113A>C		5_prime_UTR	Exon 1 of 34	ENSP00000365255.4	Q9UPS8-1
	ANKRD26	ENST00000436985.7	TSL:1	c.-113A>C		5_prime_UTR	Exon 1 of 34	ENSP00000405112.3	E7ESJ3
	ANKRD26	ENST00000968143.1		c.-113A>C		5_prime_UTR	Exon 1 of 35	ENSP00000638202.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152162 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000292 AC: 384 AN: 1314172 Hom.: 2 Cov.: 21 AF XY: 0.000282 AC XY: 184 AN XY: 651692

African (AFR) AF: 0.0000338 AC: 1 AN: 29570

American (AMR) AF: 0.00178 AC: 51 AN: 28598

Ashkenazi Jewish (ASJ) AF: 0.00105 AC: 23 AN: 21922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38044

South Asian (SAS) AF: 0.00 AC: 0 AN: 74470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34024

Middle Eastern (MID) AF: 0.00266 AC: 10 AN: 3764

European-Non Finnish (NFE) AF: 0.000256 AC: 263 AN: 1028814

Other (OTH) AF: 0.000655 AC: 36 AN: 54966

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152280 Hom.: 1 Cov.: 34 AF XY: 0.000403 AC XY: 30 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00209 AC: 32 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000438

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	ANKRD26-related disorder (1)
-	1	-	Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.6
DANN	Benign	0.80
PhyloP100		-0.41
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=174/126	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: rs886046949; hg19: chr10-27389368;