19-41220710-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_021913.5(AXL):​c.160C>A​(p.Leu54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

AXL
NM_021913.5 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62
Variant links:
Genes affected
AXL (HGNC:905): (AXL receptor tyrosine kinase) The protein encoded by this gene is a member of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase subfamily. The encoded protein possesses an extracellular domain which is composed of two immunoglobulin-like motifs at the N-terminal, followed by two fibronectin type-III motifs. It transduces signals from the extracellular matrix into the cytoplasm by binding to the vitamin K-dependent protein growth arrest-specific 6 (Gas6). This gene may be involved in several cellular functions including growth, migration, aggregation and anti-inflammation in multiple cell types. The encoded protein acts as a host cell receptor for multiple viruses, including Marburg, Ebola and Lassa viruses and is a candidate receptor for the SARS-CoV2 virus. [provided by RefSeq, Sep 2021]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.767
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXLNM_021913.5 linkc.160C>A p.Leu54Ile missense_variant Exon 2 of 20 ENST00000301178.9 NP_068713.2 P30530-1
AXLNM_001699.6 linkc.160C>A p.Leu54Ile missense_variant Exon 2 of 19 NP_001690.2 P30530-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXLENST00000301178.9 linkc.160C>A p.Leu54Ile missense_variant Exon 2 of 20 1 NM_021913.5 ENSP00000301178.3 P30530-1
AXLENST00000359092.7 linkc.160C>A p.Leu54Ile missense_variant Exon 2 of 19 1 ENSP00000351995.2 P30530-2
AXLENST00000599659.5 linkn.174C>A non_coding_transcript_exon_variant Exon 2 of 12 1
AXLENST00000594880.1 linkn.177C>A non_coding_transcript_exon_variant Exon 2 of 4 4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249740
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135056
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461412
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726938
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.00000756
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 13, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.160C>A (p.L54I) alteration is located in exon 2 (coding exon 2) of the AXL gene. This alteration results from a C to A substitution at nucleotide position 160, causing the leucine (L) at amino acid position 54 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.79
T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Pathogenic
3.0
M;M
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.95
N;N
REVEL
Uncertain
0.47
Sift
Uncertain
0.029
D;D
Sift4G
Benign
0.066
T;T
Polyphen
0.82
P;P
Vest4
0.51
MVP
0.84
MPC
0.90
ClinPred
0.96
D
GERP RS
4.6
Varity_R
0.37
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765631388; hg19: chr19-41726615; COSMIC: COSV56570647; COSMIC: COSV56570647; API