rs943720843

chr10-43119624-G-Achr10-43119624-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020975.6(RET):c.2486G>A(p.Ser829Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S829G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22770217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.2486G>A	p.Ser829Asn	missense_variant	14/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2486G>A	p.Ser829Asn	missense_variant	14/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248676 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460594 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 09, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1791991). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 829 of the RET protein (p.Ser829Asn). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2020

The c.2486G>A (p.S829N) alteration is located in exon 14 (coding exon 14) of the RET gene. This alteration results from a G to A substitution at nucleotide position 2486, causing the serine (S) at amino acid position 829 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.57	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.26
Sift	Benign	0.44	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0060	B;B
Vest4		0.28
MutPred		0.35		Loss of glycosylation at S829 (P = 0.0044);Loss of glycosylation at S829 (P = 0.0044);
MVP		0.67
MPC		0.19
ClinPred		0.22	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.39

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

Other links and lift over

dbSNP: rs943720843; hg19: chr10-43615072;