rs56132472

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004304.5(ALK):c.4338C>T(p.Thr1446Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,598,386 control chromosomes in the GnomAD database, including 10,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1446T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 972 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9749 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.22

Publications

20 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 links:

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

CLIP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-29193749-G-A is Benign according to our data. Variant chr2-29193749-G-A is described in ClinVar as Benign. ClinVar VariationId is 259273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.4338C>T	p.Thr1446Thr	synonymous_variant	Exon 29 of 29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	NM_001353765.2 link	c.1134C>T	p.Thr378Thr	synonymous_variant	Exon 10 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.4338C>T	p.Thr1446Thr	synonymous_variant	Exon 29 of 29	1	NM_004304.5	ENSP00000373700.3		Q9UM73

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15833

AN:

152102

Hom.:

973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0871

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.0827

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0928

AC:

22254

AN:

239714

AF XY:

0.0933

show subpopulations

Gnomad AFR exome

AF:

0.0882

Gnomad AMR exome

AF:

0.0526

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.110

AC:

158689

AN:

1446166

Hom.:

9749

Cov.:

AF XY:

0.108

AC XY:

77576

AN XY:

717514

show subpopulations

African (AFR)

AF:

0.0862

AC:

2837

AN:

32908

American (AMR)

AF:

0.0574

AC:

2488

AN:

43334

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

2885

AN:

25058

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39512

South Asian (SAS)

AF:

0.0404

AC:

3390

AN:

84004

European-Finnish (FIN)

AF:

0.159

AC:

8364

AN:

52738

Middle Eastern (MID)

AF:

0.102

AC:

580

AN:

5674

European-Non Finnish (NFE)

AF:

0.120

AC:

132138

AN:

1103286

Other (OTH)

AF:

0.101

AC:

6004

AN:

59652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

9073

18145

27218

36290

45363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4610

9220

13830

18440

23050

<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

AF:

0.104

AC:

15833

AN:

152220

Hom.:

972

Cov.:

AF XY:

0.104

AC XY:

7754

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0869

AC:

3612

AN:

41542

American (AMR)

AF:

0.0826

AC:

1264

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0309

AC:

149

AN:

4826

European-Finnish (FIN)

AF:

0.164

AC:

1739

AN:

10588

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8273

AN:

68004

Other (OTH)

AF:

0.106

AC:

225

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

734

1468

2203

2937

3671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.109

Hom.:

648

Bravo

AF:

0.0978

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Apr 26, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.4338C>T variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts changes of binding motifs for splicing enhancers. This variant is found in 10961/117122 control chromosomes (649 homozygotes) at a frequency of 0.0935862, which is about 224607 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Squamous cell lung carcinoma

Benign:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing;in vivo

- -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 12, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.75

(source)

DANN

Benign

0.68

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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