rs2075912

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000340058.6(RET):c.*15T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,605,984 control chromosomes in the GnomAD database, including 535,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 53076 hom., cov: 32)

Exomes 𝑓: 0.81 ( 482427 hom. )

Consequence

RET
ENST00000340058.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.43

Publications

38 publications found

Variant links:

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hirschsprung disease, susceptibility to, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Haddad syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral renal agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis
Inheritance: AR Classification: LIMITED Submitted by: G2P

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 10-43126769-T-C is Benign according to our data. Variant chr10-43126769-T-C is described in ClinVar as Benign. ClinVar VariationId is 165056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.3187+47T>C		intron_variant	Intron 19 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.3187+47T>C		intron_variant	Intron 19 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes

AF:

0.831

AC:

126321

AN:

152062

Hom.:

53013

Cov.:

show subpopulations

Gnomad AFR

AF:

0.915

Gnomad AMI

AF:

0.920

Gnomad AMR

AF:

0.805

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.499

Gnomad SAS

AF:

0.710

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.823

Gnomad OTH

AF:

0.822

GnomAD2 exomes

AF:

0.791

AC:

185804

AN:

235044

AF XY:

0.788

show subpopulations

Gnomad AFR exome

AF:

0.917

Gnomad AMR exome

AF:

0.797

Gnomad ASJ exome

AF:

0.769

Gnomad EAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.811

Gnomad NFE exome

AF:

0.827

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.812

AC:

1180522

AN:

1453804

Hom.:

482427

Cov.:

AF XY:

0.809

AC XY:

584557

AN XY:

722540

show subpopulations

African (AFR)

AF:

0.914

AC:

30445

AN:

33306

American (AMR)

AF:

0.796

AC:

34192

AN:

42944

Ashkenazi Jewish (ASJ)

AF:

0.768

AC:

19936

AN:

25960

East Asian (EAS)

AF:

0.494

AC:

19472

AN:

39428

South Asian (SAS)

AF:

0.743

AC:

63636

AN:

85652

European-Finnish (FIN)

AF:

0.807

AC:

42576

AN:

52780

Middle Eastern (MID)

AF:

0.791

AC:

4560

AN:

5762

European-Non Finnish (NFE)

AF:

0.828

AC:

917722

AN:

1107818

Other (OTH)

AF:

0.798

AC:

47983

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

11651

23302

34952

46603

58254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20906

41812

62718

83624

104530

<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:

0.831

AC:

126448

AN:

152180

Hom.:

53076

Cov.:

AF XY:

0.828

AC XY:

61607

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.915

AC:

37985

AN:

41516

American (AMR)

AF:

0.805

AC:

12327

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2654

AN:

3470

East Asian (EAS)

AF:

0.500

AC:

2578

AN:

5160

South Asian (SAS)

AF:

0.711

AC:

3426

AN:

4818

European-Finnish (FIN)

AF:

0.822

AC:

8702

AN:

10588

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.823

AC:

55968

AN:

68004

Other (OTH)

AF:

0.822

AC:

1736

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1052

2104

3156

4208

5260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.830

Hom.:

77419

Bravo

AF:

0.836

Asia WGS

AF:

0.624

AC:

2171

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2B

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pheochromocytoma

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple endocrine neoplasia, type 2

Benign:2

Aug 06, 2019

Genetics and Molecular Pathology, SA Pathology

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is the major allele (http://gnomad.broadinstitute.org/variant/10-43622217-T -C). -

Multiple endocrine neoplasia type 2A

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 01, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1 -

RET-related disorder

Benign:1

Jan 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism (auto)

(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