rs10900297

Positions:

• chr10-43077063-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The 10-43077063-C-A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 744,828 control chromosomes in the GnomAD database, including 55,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13195 hom., cov: 33)
  • Exomes 𝑓: 0.36 (42770 hom.)
• Consequence: RET NM_020975.6 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.315

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-43077063-C-A is Benign according to our data. Variant chr10-43077063-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 368899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6			upstream_gene_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8			upstream_gene_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62655 AN: 151278 Hom.: 13165 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.388

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.362 AC: 215063 AN: 593442 Hom.: 42770 Cov.: 8 AF XY: 0.363 AC XY: 104807 AN XY: 288616

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.360

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.414 AC: 62733 AN: 151386 Hom.: 13195 Cov.: 33 AF XY: 0.415 AC XY: 30709 AN XY: 74058

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.434

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.406

Alfa AF: 0.398 Hom.: 1474

Bravo AF: 0.424

Asia WGS AF: 0.360 AC: 1217 AN: 3384

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Renal hypodysplasia/aplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Multiple endocrine neoplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hirschsprung Disease, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.68

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: rs10900297; hg19: chr10-43572511;