rs3026782

Positions:

• chr10-43128657-G-A
• chr10-43128657-G-C
• chr10-43128657-G-T

Variant summary

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

The NM_020975.6(RET):​c.*388G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 382,804 control chromosomes in the GnomAD database, including 7,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2507 hom., cov: 31)
  • Exomes 𝑓: 0.19 (4596 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-43128657-G-A is Benign according to our data. Variant chr10-43128657-G-A is described in ClinVar as [Benign]. Clinvar id is 299908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.*388G>A		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.*388G>A		3_prime_UTR_variant	20/20	5	NM_020975.6	ENSP00000347942.3
RET	ENST00000615310.5	c.*1903G>A		3_prime_UTR_variant	17/17	5		ENSP00000480088.2
RET	ENST00000683007.1	n.4696G>A		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26238 AN: 151526 Hom.: 2509 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.188 AC: 43384 AN: 231160 Hom.: 4596 Cov.: 0 AF XY: 0.192 AC XY: 22728 AN XY: 118322

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.173 AC: 26245 AN: 151644 Hom.: 2507 Cov.: 31 AF XY: 0.176 AC XY: 13055 AN XY: 74034

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.181

Alfa AF: 0.194 Hom.: 806

Bravo AF: 0.173

Asia WGS AF: 0.168 AC: 584 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 12, 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 12, 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 12, 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 12, 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	-0.83
CADD	Benign	0.30
DANN	Benign	0.69

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: rs3026782; hg19: chr10-43624105; COSMIC: COSV60686309; COSMIC: COSV60686309;