20-56370332-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_198437.3(AURKA):c.1038C>A(p.Phe346Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AURKA NM_198437.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.316

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Decreases the interaction with phosphatase type 1 isoforms. (size 0) in uniprot entity AURKA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-56370332-G-T is Pathogenic according to our data. Variant chr20-56370332-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800338.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07400298).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AURKA	NM_198437.3	c.1038C>A	p.Phe346Leu	missense_variant	9/9	ENST00000395915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AURKA	ENST00000395915.8	c.1038C>A	p.Phe346Leu	missense_variant	9/9	1	NM_198437.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Aug 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	14
Dann	Benign	0.78
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.074	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	0.94	T;T;T;T;T;T;T
Vest4		0.11
MutPred		0.55		Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);Gain of catalytic residue at F346 (P = 0.0324);
MVP		0.37
ClinPred		0.091	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1455074519; hg19: chr20-54945388;