rs17028

Positions:

• chr10-43128364-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020975.6(RET):​c.*95C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,457,726 control chromosomes in the GnomAD database, including 32,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2708 hom., cov: 32)
  • Exomes 𝑓: 0.21 (29710 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.303

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]

RET (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-43128364-C-T is Benign according to our data. Variant chr10-43128364-C-T is described in ClinVar as [Benign]. Clinvar id is 299903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.*95C>T		3_prime_UTR_variant	20/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.*95C>T		3_prime_UTR_variant	20/20	5	NM_020975.6	ENSP00000347942.3
RET	ENST00000615310.5	c.*1610C>T		3_prime_UTR_variant	17/17	5		ENSP00000480088.2
RET	ENST00000683007.1	n.4403C>T		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25539 AN: 151992 Hom.: 2699 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.208 AC: 271591 AN: 1305616 Hom.: 29710 Cov.: 19 AF XY: 0.207 AC XY: 135766 AN XY: 657000

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.277

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.168 AC: 25560 AN: 152110 Hom.: 2708 Cov.: 32 AF XY: 0.174 AC XY: 12914 AN XY: 74354

Gnomad4 AFR AF: 0.0414

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.174

Alfa AF: 0.200 Hom.: 4450

Bravo AF: 0.153

Asia WGS AF: 0.177 AC: 615 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Multiple endocrine neoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.85

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: rs17028; hg19: chr10-43623812; COSMIC: COSV60689480; COSMIC: COSV60689480;