rs760625882

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_020975.6(RET):c.3200C>T(p.Pro1067Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1067S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.54

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 10-43128124-C-T is Benign according to our data. Variant chr10-43128124-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477369.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.3200C>T	p.Pro1067Leu	missense_variant	20/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.3200C>T	p.Pro1067Leu	missense_variant	20/20	5	NM_020975.6	P4	P07949-1
RET	ENST00000615310.5 linkuse as main transcript	c.*1370C>T		3_prime_UTR_variant	17/17	5
RET	ENST00000683007.1 linkuse as main transcript	n.4163C>T		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251476

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial medullary thyroid carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 10, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 29, 2020

The RET c.3200C>T; p.Pro1067Leu variant (rs760625882), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 477369). This variant is found in the general population with an overall allele frequency of 0.008% (22/282880 alleles) in the Genome Aggregation Database. The proline at codon 1067 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, this variant is not located in any predicted functional domain (InterPro). A different variant at this codon, Pro1067Ser, has been reported as an inactivating RET mutation and was identified in a fetus with unilateral renal agenesis (Skinner 2008). Due to limited information, the clinical significance of the p.Pro1067Leu variant is uncertain at this time. REFERENCES Skinner MA et al. Renal aplasia in humans is associated with RET mutations. Am J Hum Genet. 2008 Feb;82(2):344-51. -

Multiple endocrine neoplasia, type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

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

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.31

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.60

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.77

MutPred

0.39

Loss of disorder (P = 0.0219);

MVP

0.93

MPC

0.78

ClinPred

0.50

GERP RS

5.5

Varity_R

0.35

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over