rs3026785

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

2

Clinical Significance

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

Conservation

PhyloP100: 0.0130
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]

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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RETNM_020975.6 linkc.*1969T>C 3_prime_UTR_variant Exon 20 of 20 ENST00000355710.8 NP_066124.1 P07949-1A0A024R7T2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkc.*1969T>C 3_prime_UTR_variant Exon 20 of 20 5 NM_020975.6 ENSP00000347942.3 P07949-1
RETENST00000615310.5 linkc.*3484T>C 3_prime_UTR_variant Exon 17 of 17 5 ENSP00000480088.2 A0A087WWB1
RETENST00000683007.1 linkn.6277T>C non_coding_transcript_exon_variant Exon 16 of 16

Frequencies

GnomAD3 genomes
AF:
0.0438
AC:
6661
AN:
152232
Hom.:
183
Cov.:
33
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.:
0
AF XY:
0.0505
AC XY:
6037
AN XY:
119564
show subpopulations
Gnomad4 AFR exome
AF:
0.0221
AC:
156
AN:
7048
Gnomad4 AMR exome
AF:
0.0350
AC:
250
AN:
7150
Gnomad4 ASJ exome
AF:
0.0559
AC:
503
AN:
8992
Gnomad4 EAS exome
AF:
0.000988
AC:
22
AN:
22256
Gnomad4 SAS exome
AF:
0.0897
AC:
189
AN:
2106
Gnomad4 FIN exome
AF:
0.0478
AC:
916
AN:
19174
Gnomad4 NFE exome
AF:
0.0578
AC:
8807
AN:
152364
Gnomad4 Remaining exome
AF:
0.0516
AC:
814
AN:
15780
Heterozygous variant carriers
0
563
1125
1688
2250
2813
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
42
84
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.:
33
AF XY:
0.0437
AC XY:
3259
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0244
AC:
0.0243844
AN:
0.0243844
Gnomad4 AMR
AF:
0.0384
AC:
0.0384213
AN:
0.0384213
Gnomad4 ASJ
AF:
0.0536
AC:
0.0535714
AN:
0.0535714
Gnomad4 EAS
AF:
0.000963
AC:
0.000963391
AN:
0.000963391
Gnomad4 SAS
AF:
0.0890
AC:
0.0889901
AN:
0.0889901
Gnomad4 FIN
AF:
0.0399
AC:
0.0399322
AN:
0.0399322
Gnomad4 NFE
AF:
0.0557
AC:
0.0557271
AN:
0.0557271
Gnomad4 OTH
AF:
0.0577
AC:
0.057656
AN:
0.057656
Heterozygous variant carriers
0
345
690
1036
1381
1726
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
82
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

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. -

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

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. -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.44
CADD
Benign
8.0
DANN
Benign
0.81
Mutation Taster
=100/0
polymorphism (auto)

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

LitVar

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

Other links and lift over

dbSNP: rs3026785; hg19: chr10-43625686; API