chr10-43086608-T-C

Variant names:

• chr10-43086608-T-C
• rs2435357
• NM_020975.6:c.73+9277T>C

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.73+9277T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 152,304 control chromosomes in the GnomAD database, including 48,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (★★).

• Frequency: Genomes: 𝑓 0.79 (48464 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign; risk factor criteria provided, multiple submitters, no conflicts B:3 O:3
• Conservation: PhyloP100: -1.19
• Publications: 100 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-43086608-T-C is Benign according to our data. Variant chr10-43086608-T-C is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 13952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 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+9277T>C		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.73+9277T>C		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.73+9277T>C		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+9277T>C		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.73+9277T>C		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.73+9277T>C		intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.789 AC: 120018 AN: 152186 Hom.: 48396 Cov.: 34

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.789 AC: 120154 AN: 152304 Hom.: 48464 Cov.: 34 AF XY: 0.781 AC XY: 58179 AN XY: 74468

African (AFR) AF: 0.952 AC: 39584 AN: 41578

American (AMR) AF: 0.763 AC: 11680 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2426 AN: 3470

East Asian (EAS) AF: 0.544 AC: 2817 AN: 5174

South Asian (SAS) AF: 0.710 AC: 3433 AN: 4832

European-Finnish (FIN) AF: 0.636 AC: 6744 AN: 10604

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50861 AN: 68020

Other (OTH) AF: 0.775 AC: 1638 AN: 2114

Alfa AF: 0.779 Hom.: 25092

Bravo AF: 0.808

Asia WGS AF: 0.652 AC: 2268 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple endocrine neoplasia, type 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	-	Aganglionic megacolon (1)
-	-	-	Hirschsprung disease, susceptibility to, 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.60
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: rs2435357; hg19: chr10-43582056;