10-43094201-C-G

Variant names:

• chr10-43094201-C-G
• rs3128726
• NM_020975.6:c.74-6258C>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.74-6258C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 151,534 control chromosomes in the GnomAD database, including 8,803 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 0.33 (8803 hom., cov: 30)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.396
• Publications: 0 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.74-6258C>G		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.74-6258C>G		intron_variant	Intron 1 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50113 AN: 151416 Hom.: 8784 Cov.: 30

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.331 AC: 50157 AN: 151534 Hom.: 8803 Cov.: 30 AF XY: 0.333 AC XY: 24650 AN XY: 74008

African (AFR) AF: 0.214 AC: 8853 AN: 41370

American (AMR) AF: 0.397 AC: 6066 AN: 15264

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

East Asian (EAS) AF: 0.314 AC: 1588 AN: 5050

South Asian (SAS) AF: 0.413 AC: 1979 AN: 4788

European-Finnish (FIN) AF: 0.352 AC: 3712 AN: 10538

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25545 AN: 67754

Other (OTH) AF: 0.341 AC: 719 AN: 2108

Alfa AF: 0.199 Hom.: 446

Bravo AF: 0.330

Asia WGS AF: 0.355 AC: 1234 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.74
PhyloP100		-0.40
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: rs3128726; hg19: chr10-43589649;