10-43128364-C-T

Variant names:

• chr10-43128364-C-T
• rs17028
• NM_020975.6:c.*95C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020975.6(RET):​c.*95C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,457,726 control chromosomes in the GnomAD database, including 32,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2708 hom., cov: 32)
  • Exomes 𝑓: 0.21 (29710 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.303
• Publications: 25 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: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-43128364-C-T is Benign according to our data. Variant chr10-43128364-C-T is described in ClinVar as Benign. ClinVar VariationId is 299903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 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.*95C>T		3_prime_UTR	Exon 20 of 20	NP_066124.1	P07949-1
	RET	NM_001406759.1		c.*95C>T		3_prime_UTR	Exon 20 of 20	NP_001393688.1
	RET	NM_020630.7		c.*1610C>T		3_prime_UTR	Exon 19 of 19	NP_065681.1	P07949-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.*95C>T		3_prime_UTR	Exon 20 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000615310.5	TSL:5	c.*1610C>T		3_prime_UTR	Exon 17 of 17	ENSP00000480088.2	A0A087WWB1
	RET	ENST00000935253.1		c.*95C>T		3_prime_UTR	Exon 16 of 16	ENSP00000605312.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25539 AN: 151992 Hom.: 2699 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.208 AC: 271591 AN: 1305616 Hom.: 29710 Cov.: 19 AF XY: 0.207 AC XY: 135766 AN XY: 657000

African (AFR) AF: 0.0332 AC: 1006 AN: 30302

American (AMR) AF: 0.147 AC: 6428 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4288 AN: 25170

East Asian (EAS) AF: 0.215 AC: 8307 AN: 38682

South Asian (SAS) AF: 0.148 AC: 12235 AN: 82542

European-Finnish (FIN) AF: 0.277 AC: 13470 AN: 48658

Middle Eastern (MID) AF: 0.147 AC: 808 AN: 5498

European-Non Finnish (NFE) AF: 0.220 AC: 214224 AN: 975750

Other (OTH) AF: 0.196 AC: 10825 AN: 55310

GnomAD4 genome AF: 0.168 AC: 25560 AN: 152110 Hom.: 2708 Cov.: 32 AF XY: 0.174 AC XY: 12914 AN XY: 74354

African (AFR) AF: 0.0414 AC: 1717 AN: 41506

American (AMR) AF: 0.175 AC: 2672 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1196 AN: 5174

South Asian (SAS) AF: 0.144 AC: 695 AN: 4810

European-Finnish (FIN) AF: 0.294 AC: 3101 AN: 10548

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14936 AN: 67990

Other (OTH) AF: 0.174 AC: 367 AN: 2112

Alfa AF: 0.195 Hom.: 5388

Bravo AF: 0.153

Asia WGS AF: 0.177 AC: 615 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	not provided (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.30
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: rs17028; hg19: chr10-43623812; COSMIC: COSV60689480; COSMIC: COSV60689480;