chr10-43130238-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_020975.6(RET):c.*1969T>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 0.0474 in 388,468 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.044 ( 183 hom., cov: 33)

Exomes 𝑓: 0.050 ( 380 hom. )

Consequence

RET
NM_020975.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0130

Publications

13 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.*1969T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RET	ENST00000355710.8 link	c.*1969T>C	3_prime_UTR_variant	Exon 20 of 20	5	NM_020975.6	ENSP00000347942.3	P07949-1
RET	ENST00000683007.1 link	n.6277T>C	non_coding_transcript_exon_variant	Exon 16 of 16
RET	ENST00000615310.5 link	c.*3484T>C	3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000480088.2	A0A087WWB1

Frequencies

GnomAD3 genomes

AF:

0.0438

AC:

6661

AN:

152232

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.0887

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0557

Gnomad OTH

AF:

0.0587

GnomAD4 exome

AF:

0.0498

AC:

11760

AN:

236118

Hom.:

380

Cov.:

AF XY:

0.0505

AC XY:

6037

AN XY:

119564

show subpopulations

African (AFR)

AF:

0.0221

AC:

156

AN:

7048

American (AMR)

AF:

0.0350

AC:

250

AN:

7150

Ashkenazi Jewish (ASJ)

AF:

0.0559

AC:

503

AN:

8992

East Asian (EAS)

AF:

0.000988

AC:

AN:

22256

South Asian (SAS)

AF:

0.0897

AC:

189

AN:

2106

European-Finnish (FIN)

AF:

0.0478

AC:

916

AN:

19174

Middle Eastern (MID)

AF:

0.0825

AC:

103

AN:

1248

European-Non Finnish (NFE)

AF:

0.0578

AC:

8807

AN:

152364

Other (OTH)

AF:

0.0516

AC:

814

AN:

15780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

563

1125

1688

2250

2813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0438

AC:

6670

AN:

152350

Hom.:

183

Cov.:

AF XY:

0.0437

AC XY:

3259

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0244

AC:

1014

AN:

41584

American (AMR)

AF:

0.0384

AC:

588

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0536

AC:

186

AN:

3472

East Asian (EAS)

AF:

0.000963

AC:

AN:

5190

South Asian (SAS)

AF:

0.0890

AC:

430

AN:

4832

European-Finnish (FIN)

AF:

0.0399

AC:

424

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0557

AC:

3791

AN:

68028

Other (OTH)

AF:

0.0577

AC:

122

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

345

690

1036

1381

1726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0519

Hom.:

225

Bravo

AF:

0.0417

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 15, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16986122) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hirschsprung disease, protection against

Benign:1

Feb 01, 2007

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pheochromocytoma

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Renal hypodysplasia/aplasia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hirschsprung disease, susceptibility to, 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Multiple endocrine neoplasia type 2A

Benign:1

Nov 14, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Multiple endocrine neoplasia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.0

(source)

DANN

Benign

0.81

PhyloP100

0.013

Mutation Taster

=100/0

polymorphism (auto)

(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

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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