rs3026782

Variant names:

• chr10-43128657-G-A
• rs3026782
• NM_020975.6:c.*388G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43128657-G-A
• chr10-43128657-G-C
• chr10-43128657-G-T

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.*388G>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 0.182 in 382,804 control chromosomes in the GnomAD database, including 7,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2507 hom., cov: 31)
  • Exomes 𝑓: 0.19 (4596 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• Publications: 12 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=-0.83).
• BP6: Variant 10-43128657-G-A is Benign according to our data. Variant chr10-43128657-G-A is described in ClinVar as Benign. ClinVar VariationId is 299908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.*388G>A		3_prime_UTR	Exon 20 of 20	NP_066124.1
	RET	NM_001406759.1		c.*388G>A		3_prime_UTR	Exon 20 of 20	NP_001393688.1
	RET	NM_020630.7		c.*1903G>A		3_prime_UTR	Exon 19 of 19	NP_065681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.*388G>A		3_prime_UTR	Exon 20 of 20	ENSP00000347942.3
	RET	ENST00000683007.1		n.4696G>A		non_coding_transcript_exon	Exon 16 of 16
	RET	ENST00000615310.5	TSL:5	c.*1903G>A		3_prime_UTR	Exon 17 of 17	ENSP00000480088.2

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26238 AN: 151526 Hom.: 2509 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.188 AC: 43384 AN: 231160 Hom.: 4596 Cov.: 0 AF XY: 0.192 AC XY: 22728 AN XY: 118322

African (AFR) AF: 0.113 AC: 965 AN: 8564

American (AMR) AF: 0.298 AC: 2600 AN: 8728

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 1745 AN: 8654

East Asian (EAS) AF: 0.104 AC: 1866 AN: 17974

South Asian (SAS) AF: 0.248 AC: 6832 AN: 27570

European-Finnish (FIN) AF: 0.208 AC: 1565 AN: 7538

Middle Eastern (MID) AF: 0.247 AC: 255 AN: 1032

European-Non Finnish (NFE) AF: 0.182 AC: 24907 AN: 136836

Other (OTH) AF: 0.186 AC: 2649 AN: 14264

GnomAD4 genome AF: 0.173 AC: 26245 AN: 151644 Hom.: 2507 Cov.: 31 AF XY: 0.176 AC XY: 13055 AN XY: 74034

African (AFR) AF: 0.111 AC: 4577 AN: 41312

American (AMR) AF: 0.248 AC: 3782 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 703 AN: 3472

East Asian (EAS) AF: 0.110 AC: 565 AN: 5142

South Asian (SAS) AF: 0.236 AC: 1134 AN: 4800

European-Finnish (FIN) AF: 0.233 AC: 2435 AN: 10456

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12449 AN: 67924

Other (OTH) AF: 0.181 AC: 381 AN: 2102

Alfa AF: 0.190 Hom.: 876

Bravo AF: 0.173

Asia WGS AF: 0.168 AC: 584 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.83
CADD	Benign	0.30
DANN	Benign	0.69
PhyloP100		-1.2
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: rs3026782; hg19: chr10-43624105; COSMIC: COSV60686309; COSMIC: COSV60686309;