10-43129385-T-C

Position:

• chr10-43129385-T-C

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.*1116T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 233,622 control chromosomes in the GnomAD database, including 5,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3845 hom., cov: 32)
  • Exomes 𝑓: 0.22 (2067 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.835

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=-0.45).
• BP6: Variant 10-43129385-T-C is Benign according to our data. Variant chr10-43129385-T-C is described in ClinVar as [Benign]. Clinvar id is 299925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) 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.*1116T>C		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.*1116T>C		3_prime_UTR_variant	20/20	5	NM_020975.6	ENSP00000347942.3
RET	ENST00000615310.5	c.*2631T>C		3_prime_UTR_variant	17/17	5		ENSP00000480088.2
RET	ENST00000683007.1	n.5424T>C		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33459 AN: 152100 Hom.: 3833 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.224 AC: 18221 AN: 81404 Hom.: 2067 Cov.: 0 AF XY: 0.225 AC XY: 8440 AN XY: 37474

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.220 AC: 33501 AN: 152218 Hom.: 3845 Cov.: 32 AF XY: 0.223 AC XY: 16609 AN XY: 74424

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.224

Alfa AF: 0.235 Hom.: 5334

Bravo AF: 0.211

Asia WGS AF: 0.194 AC: 676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

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. -

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. -

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. -

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	-0.45
CADD	Benign	14
DANN	Benign	0.87

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: rs2435355; hg19: chr10-43624833; COSMIC: COSV60707325; COSMIC: COSV60707325;