ENST00000340058.6:c.*15T>C

Variant names:

• chr10-43126769-T-C
• rs2075912
• ENST00000340058.6:c.*15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000340058.6(RET):​c.*15T>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 0.814 in 1,605,984 control chromosomes in the GnomAD database, including 535,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53076 hom., cov: 32)
  • Exomes 𝑓: 0.81 (482427 hom.)
• Consequence: RET ENST00000340058.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.43
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-43126769-T-C is Benign according to our data. Variant chr10-43126769-T-C is described in ClinVar as Benign. ClinVar VariationId is 165056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000340058.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.3187+47T>C		intron	N/A	NP_066124.1	P07949-1
	RET	NM_020630.7		c.*15T>C		3_prime_UTR	Exon 19 of 19	NP_065681.1	P07949-2
	RET	NM_001406764.1		c.*15T>C		3_prime_UTR	Exon 19 of 19	NP_001393693.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000340058.6	TSL:1	c.*15T>C		3_prime_UTR	Exon 19 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000355710.8	TSL:5 MANE Select	c.3187+47T>C		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000713926.1		c.*15T>C		3_prime_UTR	Exon 19 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126321 AN: 152062 Hom.: 53013 Cov.: 32

Gnomad AFR AF: 0.915

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.822

GnomAD2 exomes AF: 0.791 AC: 185804 AN: 235044 AF XY: 0.788

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.827

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.812 AC: 1180522 AN: 1453804 Hom.: 482427 Cov.: 48 AF XY: 0.809 AC XY: 584557 AN XY: 722540

African (AFR) AF: 0.914 AC: 30445 AN: 33306

American (AMR) AF: 0.796 AC: 34192 AN: 42944

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 19936 AN: 25960

East Asian (EAS) AF: 0.494 AC: 19472 AN: 39428

South Asian (SAS) AF: 0.743 AC: 63636 AN: 85652

European-Finnish (FIN) AF: 0.807 AC: 42576 AN: 52780

Middle Eastern (MID) AF: 0.791 AC: 4560 AN: 5762

European-Non Finnish (NFE) AF: 0.828 AC: 917722 AN: 1107818

Other (OTH) AF: 0.798 AC: 47983 AN: 60154

GnomAD4 genome AF: 0.831 AC: 126448 AN: 152180 Hom.: 53076 Cov.: 32 AF XY: 0.828 AC XY: 61607 AN XY: 74412

African (AFR) AF: 0.915 AC: 37985 AN: 41516

American (AMR) AF: 0.805 AC: 12327 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2654 AN: 3470

East Asian (EAS) AF: 0.500 AC: 2578 AN: 5160

South Asian (SAS) AF: 0.711 AC: 3426 AN: 4818

European-Finnish (FIN) AF: 0.822 AC: 8702 AN: 10588

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.823 AC: 55968 AN: 68004

Other (OTH) AF: 0.822 AC: 1736 AN: 2112

Alfa AF: 0.830 Hom.: 77419

Bravo AF: 0.836

Asia WGS AF: 0.624 AC: 2171 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Multiple endocrine neoplasia type 2B (2)
-	-	2	Multiple endocrine neoplasia, type 2 (2)
-	-	2	Pheochromocytoma (2)
-	-	1	Multiple endocrine neoplasia type 2A (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.70
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2075912; hg19: chr10-43622217; COSMIC: COSV60689472;