rs1280250127

Positions:

• chr10-43114657-G-A
• chr10-43114657-G-C

Variant summary

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

The NM_020975.6(RET):​c.2057G>A​(p.Ser686Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,740 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.75

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2057G>A	p.Ser686Asn	missense_variant	11/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2057G>A	p.Ser686Asn	missense_variant	11/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250578 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460740 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.027	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.65	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.091	T;T
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.17		Loss of phosphorylation at S686 (P = 0.0298);Loss of phosphorylation at S686 (P = 0.0298);
MVP		0.77
MPC		0.66
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.74

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: rs1280250127; hg19: chr10-43610105;