NM_020975.6:c.74-126G>T

Variant names:

• chr10-43100333-G-T
• rs2565206
• NM_020975.6:c.74-126G>T

Variant summary

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

The NM_020975.6(RET):​c.74-126G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,104,434 control chromosomes in the GnomAD database, including 65,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12401 hom., cov: 33)
  • Exomes 𝑓: 0.33 (53340 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0150
• Publications: 15 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: Orphanet, G2P
• multiple endocrine neoplasia type 2A

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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=-0.87).
• BP6: Variant 10-43100333-G-T is Benign according to our data. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100333-G-T is described in CliVar as Benign. Clinvar id is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.74-126G>T		intron_variant	Intron 1 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.74-126G>T		intron_variant	Intron 1 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57777 AN: 151560 Hom.: 12369 Cov.: 33

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.326 AC: 310614 AN: 952784 Hom.: 53340 AF XY: 0.321 AC XY: 157441 AN XY: 490342

African (AFR) AF: 0.601 AC: 13577 AN: 22584

American (AMR) AF: 0.263 AC: 9517 AN: 36130

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 7333 AN: 22314

East Asian (EAS) AF: 0.132 AC: 4588 AN: 34864

South Asian (SAS) AF: 0.218 AC: 15260 AN: 70082

European-Finnish (FIN) AF: 0.254 AC: 10354 AN: 40774

Middle Eastern (MID) AF: 0.286 AC: 951 AN: 3326

European-Non Finnish (NFE) AF: 0.345 AC: 234702 AN: 679366

Other (OTH) AF: 0.331 AC: 14332 AN: 43344

GnomAD4 genome AF: 0.381 AC: 57854 AN: 151650 Hom.: 12401 Cov.: 33 AF XY: 0.371 AC XY: 27505 AN XY: 74102

African (AFR) AF: 0.590 AC: 24394 AN: 41364

American (AMR) AF: 0.321 AC: 4892 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1130 AN: 3464

East Asian (EAS) AF: 0.112 AC: 576 AN: 5154

South Asian (SAS) AF: 0.198 AC: 951 AN: 4806

European-Finnish (FIN) AF: 0.234 AC: 2436 AN: 10392

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22406 AN: 67910

Other (OTH) AF: 0.367 AC: 769 AN: 2098

Alfa AF: 0.286 Hom.: 1713

Bravo AF: 0.398

Asia WGS AF: 0.187 AC: 651 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, type 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		-0.015
PromoterAI		-0.0046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2565206; hg19: chr10-43595781;