chr10-43083625-C-T

Variant names:

• chr10-43083625-C-T
• rs2506020
• NM_020975.6:c.73+6294C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020975.6(RET):​c.73+6294C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,776 control chromosomes in the GnomAD database, including 10,471 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10471 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.73+6294C>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.73+6294C>T		intron_variant	Intron 1 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55802 AN: 151658 Hom.: 10449 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.390

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.369

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.368 AC: 55849 AN: 151776 Hom.: 10471 Cov.: 33 AF XY: 0.370 AC XY: 27444 AN XY: 74146

African (AFR) AF: 0.312 AC: 12952 AN: 41506

American (AMR) AF: 0.415 AC: 6326 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3464

East Asian (EAS) AF: 0.323 AC: 1632 AN: 5056

South Asian (SAS) AF: 0.426 AC: 2030 AN: 4760

European-Finnish (FIN) AF: 0.363 AC: 3833 AN: 10552

Middle Eastern (MID) AF: 0.403 AC: 117 AN: 290

European-Non Finnish (NFE) AF: 0.392 AC: 26597 AN: 67890

Other (OTH) AF: 0.371 AC: 779 AN: 2098

Alfa AF: 0.362 Hom.: 1236

Bravo AF: 0.370

Asia WGS AF: 0.361 AC: 1253 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.61
PhyloP100		-0.22
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: rs2506020; hg19: chr10-43579073;