10-43082425-A-T

Variant names:

• chr10-43082425-A-T
• rs2506016
• NM_020975.6:c.73+5094A>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+5094A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 152,126 control chromosomes in the GnomAD database, including 10,459 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 (10459 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.671
• 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=-0.64).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.405 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.73+5094A>T		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.73+5094A>T		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.73+5094A>T		intron	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.73+5094A>T		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.73+5094A>T		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.73+5094A>T		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55777 AN: 152008 Hom.: 10437 Cov.: 34

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.367 AC: 55824 AN: 152126 Hom.: 10459 Cov.: 34 AF XY: 0.369 AC XY: 27432 AN XY: 74348

African (AFR) AF: 0.312 AC: 12938 AN: 41492

American (AMR) AF: 0.413 AC: 6321 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1638 AN: 5178

South Asian (SAS) AF: 0.421 AC: 2027 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3844 AN: 10602

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26573 AN: 67950

Other (OTH) AF: 0.369 AC: 781 AN: 2114

Alfa AF: 0.371 Hom.: 1308

Bravo AF: 0.370

Asia WGS AF: 0.359 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.6
DANN	Benign	0.77
PhyloP100		0.67
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: rs2506016; hg19: chr10-43577873;