NM_020975.6:c.73+2157T>C

Variant names:

• chr10-43079488-T-C
• rs2506011
• NM_020975.6:c.73+2157T>C

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+2157T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 152,140 control chromosomes in the GnomAD database, including 10,864 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 0.38 (10864 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.356
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.73+2157T>C		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+2157T>C		intron_variant	Intron 1 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57069 AN: 152022 Hom.: 10840 Cov.: 33

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.375 AC: 57122 AN: 152140 Hom.: 10864 Cov.: 33 AF XY: 0.377 AC XY: 28043 AN XY: 74390

African (AFR) AF: 0.341 AC: 14167 AN: 41492

American (AMR) AF: 0.416 AC: 6371 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1636 AN: 5162

South Asian (SAS) AF: 0.416 AC: 2004 AN: 4822

European-Finnish (FIN) AF: 0.362 AC: 3838 AN: 10596

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26604 AN: 67978

Other (OTH) AF: 0.377 AC: 798 AN: 2114

Alfa AF: 0.388 Hom.: 6625

Bravo AF: 0.379

Asia WGS AF: 0.360 AC: 1251 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.73
PhyloP100		-0.36
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: rs2506011; hg19: chr10-43574936;