rs748978993

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004304.5(ALK):c.233C>T(p.Ser78Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,451,312 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S78W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.20

Publications

2 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

ALK links:

ENSG00000233862 (HGNC:):

ENSG00000233862 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07039189).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.233C>T	p.Ser78Leu	missense_variant	Exon 1 of 29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 link	n.1160C>T		non_coding_transcript_exon_variant	Exon 1 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALK	ENST00000389048.8 link	c.233C>T	p.Ser78Leu	missense_variant	Exon 1 of 29	1	NM_004304.5	ENSP00000373700.3	Q9UM73
ENSG00000233862	ENST00000669284.1 link	n.157+34822C>T		intron_variant	Intron 1 of 1
ENSG00000233862	ENST00000769926.1 link	n.534+5792C>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000222

AC:

AN:

225332

AF XY:

0.0000244

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000508

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1451312

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

43622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25850

East Asian (EAS)

AF:

0.00

AC:

AN:

39186

South Asian (SAS)

AF:

0.00

AC:

AN:

84342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000903

AC:

AN:

1107526

Other (OTH)

AF:

0.00

AC:

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:2

Nov 08, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the ALK protein (p.Ser78Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1789837). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is present in population databases (rs748978993, gnomAD 0.005%). -

not provided

Uncertain:1

Sep 23, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S78L variant (also known as c.233C>T), located in coding exon 1 of the ALK gene, results from a C to T substitution at nucleotide position 233. The serine at codon 78 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.66

M_CAP

Benign

0.036

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.38

REVEL

Benign

0.030

Sift

Uncertain

0.029

Sift4G

Uncertain

0.016

Polyphen

0.0020

Vest4

0.13

MutPred

0.26

Loss of phosphorylation at S78 (P = 0.0171);

MVP

0.34

MPC

0.15

ClinPred

0.13

GERP RS

3.5

Varity_R

0.062

gMVP

0.17

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over