20-56386407-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198437.3(AURKA):c.169A>G(p.Ile57Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,986 control chromosomes in the GnomAD database, including 575,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.84 (54283 hom., cov: 31)
  • Exomes 𝑓: 0.84 (520862 hom.)
• Consequence: AURKA NM_198437.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.556

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0621073E-7).
• BP6: Variant 20-56386407-T-C is Benign according to our data. Variant chr20-56386407-T-C is described in ClinVar as [Benign]. Clinvar id is 3059051.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AURKA	NM_198437.3	c.169A>G	p.Ile57Val	missense_variant	3/9	ENST00000395915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AURKA	ENST00000395915.8	c.169A>G	p.Ile57Val	missense_variant	3/9	1	NM_198437.3	P1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128366 AN: 152010 Hom.: 54229 Cov.: 31

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.892

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.860

GnomAD3 exomes AF: 0.851 AC: 213970 AN: 251486 Hom.: 91168 AF XY: 0.848 AC XY: 115283 AN XY: 135920

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.853

Gnomad EAS exome AF: 0.878

Gnomad SAS exome AF: 0.859

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.844 AC: 1233537 AN: 1461858 Hom.: 520862 Cov.: 88 AF XY: 0.844 AC XY: 613833 AN XY: 727230

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.912

Gnomad4 ASJ exome AF: 0.858

Gnomad4 EAS exome AF: 0.871

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.810

Gnomad4 NFE exome AF: 0.840

Gnomad4 OTH exome AF: 0.847

GnomAD4 genome AF: 0.845 AC: 128476 AN: 152128 Hom.: 54283 Cov.: 31 AF XY: 0.843 AC XY: 62696 AN XY: 74386

Gnomad4 AFR AF: 0.838

Gnomad4 AMR AF: 0.887

Gnomad4 ASJ AF: 0.865

Gnomad4 EAS AF: 0.880

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.838

Gnomad4 OTH AF: 0.856

Alfa AF: 0.838 Hom.: 136903

Bravo AF: 0.850

TwinsUK AF: 0.841 AC: 3119

ALSPAC AF: 0.847 AC: 3265

ESP6500AA AF: 0.838 AC: 3693

ESP6500EA AF: 0.838 AC: 7203

ExAC AF: 0.848 AC: 102977

Asia WGS AF: 0.872 AC: 3034 AN: 3478

EpiCase AF: 0.829

EpiControl AF: 0.826

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AURKA-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.032
Dann	Benign	0.21
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	6.1e-7	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.0	.;.;.;.;.;.;.;B;B;B;B;B;.
Vest4		0.010
ClinPred		0.00020	T
GERP RS		2.0
gMVP		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1047972; hg19: chr20-54961463; COSMIC: COSV100452806;