rs377767428

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_020975.6(RET):​c.2647G>A​(p.Ala883Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A883F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.89
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RETNM_020975.6 linkuse as main transcriptc.2647G>A p.Ala883Thr missense_variant 15/20 ENST00000355710.8 NP_066124.1 P07949-1A0A024R7T2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.2647G>A p.Ala883Thr missense_variant 15/205 NM_020975.6 ENSP00000347942.3 P07949-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461696
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 31, 2021This sequence change replaces alanine with threonine at codon 883 of the RET protein (p.Ala883Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 15531548, 25440022, 28946813). ClinVar contains an entry for this variant (Variation ID: 24958). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 21810974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ala883 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9294615, 10679286, 21186952, 25244518, 28323957). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMar 09, 2023This missense variant replaces alanine with threonine at codon 883 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant has low transforming activity based on focal formation, soft-agar growth and growth rate assays in ex vivo cells (PMID: 21810974). This variant has been reported in four individuals from three families affected with medullary thyroid cancer that include two unrelated heterozygous carriers (PMID: 28946813, 29515777, 31510104) and two siblings from a consanguineous family who are homozygous for this variant (PMID: 15531548, 31510104). At least three heterozygous carriers from this consanguineous family who are older than the affected siblings are asymptomatic for thyroid-related disease (PMID: 15531548). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2024The p.A883T variant (also known as c.2647G>A), located in coding exon 15 of the RET gene, results from a G to A substitution at nucleotide position 2647. The alanine at codon 883 is replaced by threonine, an amino acid with similar properties. This variant has been reported in the homozyous state in two brothers with medullary thyroid cancer (MTC) diagnosed in their fifties; however, four relatives who were heterozygous for the variant did not have MTC (Elisei R et al. J. Clin. Endocrinol. Metab. 2004 Nov;89:5823-7). Studies of familial MTC, as well as apparently sporadic MTC cases, have identified this variant (Romei C et al. Eur. J. Endocrinol. 2010 Aug;163:301-8; Romei C et al. Clin. Endocrinol. (Oxf). 2015 Jun;82:892-9; Lebeault M et al. Thyroid. 2017 12;27:1511-1522; Romei C et al. Oncotarget. 2018 Feb;9:9875-9884). In vitro assays analyzing the transforming activity of RET variants, found that this variant had an intermediate number of focus formation units, therefore described as having low or non-transforming potential (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
-0.80
N;N
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Pathogenic
0.77
Sift
Benign
0.10
T;D
Sift4G
Benign
0.20
T;T
Polyphen
1.0
D;D
Vest4
0.49
MutPred
0.86
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.95
MPC
0.54
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.84
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs377767428; hg19: chr10-43615568; API