20-56386485-A-T

Position:

• chr20-56386485-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198437.3(AURKA):​c.91T>A​(p.Phe31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,914 control chromosomes in the GnomAD database, including 50,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4562 hom., cov: 33)
  • Exomes 𝑓: 0.24 (45982 hom.)
• Consequence: AURKA NM_198437.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.555

Genes affected

AURKA (HGNC:11393): (aurora kinase A) The protein encoded by this gene is a cell cycle-regulated kinase that appears to be involved in microtubule formation and/or stabilization at the spindle pole during chromosome segregation. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. This gene may play a role in tumor development and progression. A processed pseudogene of this gene has been found on chromosome 1, and an unprocessed pseudogene has been found on chromosome 10. Multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5131277E-6).
• BP6: Variant 20-56386485-A-T is Benign according to our data. Variant chr20-56386485-A-T is described in ClinVar as [Benign]. Clinvar id is 6642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AURKA	NM_198437.3	c.91T>A	p.Phe31Ile	missense_variant	3/9	ENST00000395915.8	NP_940839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AURKA	ENST00000395915.8	c.91T>A	p.Phe31Ile	missense_variant	3/9	1	NM_198437.3	ENSP00000379251.3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33952 AN: 152018 Hom.: 4556 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.278 AC: 69789 AN: 251444 Hom.: 11713 AF XY: 0.274 AC XY: 37297 AN XY: 135904

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.236 AC: 345594 AN: 1461776 Hom.: 45982 Cov.: 41 AF XY: 0.238 AC XY: 172899 AN XY: 727194

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.666

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.223 AC: 33974 AN: 152138 Hom.: 4562 Cov.: 33 AF XY: 0.230 AC XY: 17118 AN XY: 74378

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.222

Alfa AF: 0.181 Hom.: 932

Bravo AF: 0.222

TwinsUK AF: 0.227 AC: 841

ALSPAC AF: 0.220 AC: 848

ESP6500AA AF: 0.132 AC: 583

ESP6500EA AF: 0.217 AC: 1865

ExAC AF: 0.273 AC: 33184

Asia WGS AF: 0.453 AC: 1576 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 23803310, 21412660, 22213102, 15867347, 15271856, 21198377, 20002563, 17219423, 17898866, 24349361, 15087379, 28903390, 25697104) -

AURKA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Colon cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.59
DANN	Benign	0.76
DEOGEN2	Benign	0.0098	.;.;.;.;.;.;.;.;T;.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.43	.;.;.;.;.;.;.;T;T;T;T;T;T
MetaRNN	Benign	0.0000035	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N;N;N;N;N;N;D;N
REVEL	Benign	0.052
Sift	Benign	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.0	.;.;.;.;.;.;.;B;B;B;B;B;.
Vest4		0.065
ClinPred		0.00052	T
GERP RS		-7.5
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273535; hg19: chr20-54961541; COSMIC: COSV57167236;