NM_020975.6:c.74-7594A>G

Variant names:

• chr10-43092865-A-G
• rs752975
• NM_020975.6:c.74-7594A>G

Variant summary

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

The NM_020975.6(RET):​c.74-7594A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,094 control chromosomes in the GnomAD database, including 11,591 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 0.39 (11591 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.74-7594A>G		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.74-7594A>G		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.74-7594A>G		intron	N/A	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.74-7594A>G		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.74-7594A>G		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.74-7594A>G		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58515 AN: 151976 Hom.: 11571 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.385 AC: 58574 AN: 152094 Hom.: 11591 Cov.: 33 AF XY: 0.388 AC XY: 28839 AN XY: 74328

African (AFR) AF: 0.296 AC: 12294 AN: 41500

American (AMR) AF: 0.430 AC: 6570 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1303 AN: 3472

East Asian (EAS) AF: 0.434 AC: 2243 AN: 5168

South Asian (SAS) AF: 0.511 AC: 2465 AN: 4822

European-Finnish (FIN) AF: 0.393 AC: 4141 AN: 10548

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28051 AN: 67980

Other (OTH) AF: 0.397 AC: 839 AN: 2114

Alfa AF: 0.380 Hom.: 1427

Bravo AF: 0.384

Asia WGS AF: 0.464 AC: 1614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.82
PhyloP100		0.10
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: rs752975; hg19: chr10-43588313;