NM_004304.5:c.117G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004304.5(ALK):​c.117G>T​(p.Gln39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q39P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Publications

0 publications found
Variant links:
Genes affected
ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]
ALK Gene-Disease associations (from GenCC):
  • neuroblastoma, susceptibility to, 3
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.2533301).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALKNM_004304.5 linkc.117G>T p.Gln39His missense_variant Exon 1 of 29 ENST00000389048.8 NP_004295.2 Q9UM73B6D4Y2
ALKXR_001738688.3 linkn.1044G>T non_coding_transcript_exon_variant Exon 1 of 18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkc.117G>T p.Gln39His missense_variant Exon 1 of 29 1 NM_004304.5 ENSP00000373700.3 Q9UM73
ENSG00000233862ENST00000669284.1 linkn.157+34706G>T intron_variant Intron 1 of 1
ENSG00000233862ENST00000769926.1 linkn.534+5676G>T intron_variant Intron 4 of 4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455218
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
723650
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33402
American (AMR)
AF:
0.00
AC:
0
AN:
44542
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26034
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39570
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85962
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49820
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
9.01e-7
AC:
1
AN:
1110130
Other (OTH)
AF:
0.00
AC:
0
AN:
60034
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1
Sep 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 39 of the ALK protein (p.Gln39His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.010
Eigen_PC
Benign
0.067
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.62
T
M_CAP
Pathogenic
0.29
D
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
0.69
N
PhyloP100
2.2
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.49
N
REVEL
Benign
0.12
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.014
D
Polyphen
0.94
P
Vest4
0.15
MutPred
0.13
Gain of glycosylation at P40 (P = 0.1609);
MVP
0.57
MPC
0.67
ClinPred
0.74
D
GERP RS
4.3
Varity_R
0.18
gMVP
0.23
Mutation Taster
=71/29
polymorphism

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

Other links and lift over

dbSNP: rs1225169683; hg19: chr2-30143409; COSMIC: COSV66572746; API