rs3026785

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

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. Variant has been reported in ClinVar as Likely benign (★★).

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: G2P, Orphanet
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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 -18 ACMG points.

BP4

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

BP6

Variant 10-43130238-T-C is Benign according to our data. Variant chr10-43130238-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RET	NM_020975.6	MANE Select	c.*1969T>C	3_prime_UTR	Exon 20 of 20	NP_066124.1	P07949-1
RET	NM_001406743.1		c.*737T>C	3_prime_UTR	Exon 21 of 21	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.*587T>C	3_prime_UTR	Exon 20 of 20	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RET	ENST00000355710.8	TSL:5 MANE Select	c.*1969T>C	3_prime_UTR	Exon 20 of 20	ENSP00000347942.3	P07949-1
RET	ENST00000615310.5	TSL:5	c.*3484T>C	3_prime_UTR	Exon 17 of 17	ENSP00000480088.2	A0A087WWB1
RET	ENST00000935253.1		c.*1969T>C	3_prime_UTR	Exon 16 of 16	ENSP00000605312.1

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia (1)

Multiple endocrine neoplasia type 2A (1)

Pheochromocytoma (1)

Renal hypodysplasia/aplasia 1 (1)

Hirschsprung disease, protection against (1)

Computational scores

Source: dbNSFP v4.9

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over