19-41220722-C-A

Variant names:

• chr19-41220722-C-A
• rs200868176
• NM_021913.5:c.172C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021913.5(AXL):​c.172C>A​(p.Leu58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L58V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AXL NM_021913.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19261739).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021913.5. 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
	AXL	NM_021913.5	MANE Select	c.172C>A	p.Leu58Ile	missense	Exon 2 of 20	NP_068713.2
	AXL	NM_001699.6		c.172C>A	p.Leu58Ile	missense	Exon 2 of 19	NP_001690.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXL	ENST00000301178.9	TSL:1 MANE Select	c.172C>A	p.Leu58Ile	missense	Exon 2 of 20	ENSP00000301178.3	P30530-1
	AXL	ENST00000359092.7	TSL:1	c.172C>A	p.Leu58Ile	missense	Exon 2 of 19	ENSP00000351995.2	P30530-2
	AXL	ENST00000599659.5	TSL:1	n.186C>A		non_coding_transcript_exon	Exon 2 of 12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.12
Sift	Benign	0.42	T
Sift4G	Benign	1.0	T
Polyphen		0.35	B
Vest4		0.43
MutPred		0.41		Loss of disorder (P = 0.1371)
MVP		0.47
MPC		0.72
ClinPred		0.52	D
GERP RS		3.5
Varity_R		0.32
gMVP		0.18
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200868176; hg19: chr19-41726627;