ENST00000935252.1:c.-200A>G

Variant names:

• chr10-43077059-A-G
• rs10900296
• ENST00000935252.1:c.-200A>G

Variant summary

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

The ENST00000935252.1(RET):​c.-200A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 652,438 control chromosomes in the GnomAD database, including 186,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45255 hom., cov: 31)
  • Exomes 𝑓: 0.75 (141070 hom.)
• Consequence: RET ENST00000935252.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.336
• Publications: 21 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

ENSG00000303432 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-43077059-A-G is Benign according to our data. Variant chr10-43077059-A-G is described in ClinVar as Benign. ClinVar VariationId is 368898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000935252.1. 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.-200A>G		upstream_gene	N/A	NP_066124.1
	RET	NM_001406743.1		c.-200A>G		upstream_gene	N/A	NP_001393672.1
	RET	NM_001406744.1		c.-200A>G		upstream_gene	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000935252.1		c.-200A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000605311.1
	RET	ENST00000935252.1		c.-200A>G		5_prime_UTR	Exon 1 of 15	ENSP00000605311.1
	ENSG00000303432	ENST00000794441.1		n.90T>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116140 AN: 151032 Hom.: 45207 Cov.: 31

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.705

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.761

GnomAD4 exome AF: 0.749 AC: 375266 AN: 501298 Hom.: 141070 Cov.: 7 AF XY: 0.749 AC XY: 183227 AN XY: 244788

African (AFR) AF: 0.877 AC: 9494 AN: 10826

American (AMR) AF: 0.751 AC: 4089 AN: 5448

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 6689 AN: 9324

East Asian (EAS) AF: 0.600 AC: 11539 AN: 19234

South Asian (SAS) AF: 0.724 AC: 10101 AN: 13956

European-Finnish (FIN) AF: 0.682 AC: 10804 AN: 15852

Middle Eastern (MID) AF: 0.750 AC: 1207 AN: 1610

European-Non Finnish (NFE) AF: 0.757 AC: 304169 AN: 402020

Other (OTH) AF: 0.746 AC: 17174 AN: 23028

GnomAD4 genome AF: 0.769 AC: 116250 AN: 151140 Hom.: 45255 Cov.: 31 AF XY: 0.763 AC XY: 56329 AN XY: 73848

African (AFR) AF: 0.871 AC: 36029 AN: 41356

American (AMR) AF: 0.757 AC: 11520 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2419 AN: 3452

East Asian (EAS) AF: 0.538 AC: 2715 AN: 5050

South Asian (SAS) AF: 0.714 AC: 3427 AN: 4802

European-Finnish (FIN) AF: 0.643 AC: 6620 AN: 10288

Middle Eastern (MID) AF: 0.703 AC: 204 AN: 290

European-Non Finnish (NFE) AF: 0.753 AC: 50968 AN: 67672

Other (OTH) AF: 0.760 AC: 1594 AN: 2098

Alfa AF: 0.669 Hom.: 2129

Bravo AF: 0.784

Asia WGS AF: 0.635 AC: 2138 AN: 3368

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hirschsprung Disease, Dominant (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	-0.83
CADD	Benign	8.5
DANN	Benign	0.47
PhyloP100		0.34
PromoterAI		0.69	Over-expression
Mutation Taster		=291/9	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: rs10900296; hg19: chr10-43572507;