NM_004304.5:c.2759G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP3_ModerateBP6_Moderate

The NM_004304.5(ALK):c.2759G>T(p.Gly920Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G920S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000030 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.35

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

BP6

Variant 2-29228940-C-A is Benign according to our data. Variant chr2-29228940-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3524397.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.2759G>T	p.Gly920Val	missense_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.3668+18G>T		intron_variant	Intron 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.2759G>T	p.Gly920Val	missense_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.1628G>T	p.Gly543Val	missense_variant	Exon 15 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.0000305

AC:

AN:

98516

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000116

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000187

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000781

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

243688

AF XY:

0.0000606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000893

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000236

AC:

175

AN:

741622

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

AN XY:

375390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000114

AC:

AN:

17568

American (AMR)

AF:

0.000496

AC:

AN:

26232

Ashkenazi Jewish (ASJ)

AF:

0.000130

AC:

AN:

15412

East Asian (EAS)

AF:

0.000493

AC:

AN:

24358

South Asian (SAS)

AF:

0.000708

AC:

AN:

52294

European-Finnish (FIN)

AF:

0.000253

AC:

AN:

35524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3696

European-Non Finnish (NFE)

AF:

0.000174

AC:

AN:

535698

Other (OTH)

AF:

0.000227

AC:

AN:

30840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

109

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000304

AC:

AN:

98534

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

47882

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26098

American (AMR)

AF:

0.000116

AC:

AN:

8634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2428

East Asian (EAS)

AF:

0.00

AC:

AN:

3474

South Asian (SAS)

AF:

0.00

AC:

AN:

3160

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

5356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47192

Other (OTH)

AF:

0.000774

AC:

AN:

1292

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000313

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Aug 21, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.7

H;.

PhyloP100

7.4

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.3

D;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0050

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.58

Loss of disorder (P = 0.0177);.;

MVP

0.73

MPC

0.79

ClinPred

0.87

GERP RS

5.2

Varity_R

0.79

gMVP

0.90

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over