rs76759170

Variant names:

• chr10-43129860-G-A
• rs76759170
• NM_020975.6:c.*1591G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020975.6(RET):​c.*1591G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 396,966 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (142 hom., cov: 33)
  • Exomes 𝑓: 0.044 (317 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.487
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-43129860-G-A is Benign according to our data. Variant chr10-43129860-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 299937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0801 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.*1591G>A		3_prime_UTR	Exon 20 of 20	NP_066124.1
	RET	NM_001406743.1		c.*359G>A		3_prime_UTR	Exon 21 of 21	NP_001393672.1
	RET	NM_001406744.1		c.*209G>A		3_prime_UTR	Exon 20 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.*1591G>A		3_prime_UTR	Exon 20 of 20	ENSP00000347942.3
	RET	ENST00000615310.5	TSL:5	c.*3106G>A		3_prime_UTR	Exon 17 of 17	ENSP00000480088.2
	RET	ENST00000935253.1		c.*1591G>A		3_prime_UTR	Exon 16 of 16	ENSP00000605312.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5916 AN: 152144 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0476

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0444 AC: 10873 AN: 244702 Hom.: 317 Cov.: 0 AF XY: 0.0453 AC XY: 5612 AN XY: 124016

African (AFR) AF: 0.0208 AC: 149 AN: 7154

American (AMR) AF: 0.0322 AC: 238 AN: 7380

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 522 AN: 9198

East Asian (EAS) AF: 0.00101 AC: 23 AN: 22750

South Asian (SAS) AF: 0.0904 AC: 246 AN: 2720

European-Finnish (FIN) AF: 0.0388 AC: 813 AN: 20946

Middle Eastern (MID) AF: 0.0836 AC: 108 AN: 1292

European-Non Finnish (NFE) AF: 0.0510 AC: 8003 AN: 157014

Other (OTH) AF: 0.0475 AC: 771 AN: 16248

GnomAD4 genome AF: 0.0389 AC: 5925 AN: 152264 Hom.: 142 Cov.: 33 AF XY: 0.0392 AC XY: 2918 AN XY: 74436

African (AFR) AF: 0.0232 AC: 963 AN: 41560

American (AMR) AF: 0.0365 AC: 558 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3468

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.0870 AC: 420 AN: 4828

European-Finnish (FIN) AF: 0.0315 AC: 333 AN: 10584

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0476 AC: 3240 AN: 68016

Other (OTH) AF: 0.0530 AC: 112 AN: 2114

Alfa AF: 0.0404 Hom.: 45

Bravo AF: 0.0377

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.8
DANN	Benign	0.75
PhyloP100		0.49
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: rs76759170; hg19: chr10-43625308;