rs9282834

Variant names:

• chr10-43111408-G-A
• rs9282834
• NM_020975.6:c.1465G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43111408-G-A
• chr10-43111408-G-C
• chr10-43111408-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020975.6(RET):​c.1465G>A​(p.Asp489Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,613,718 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D489E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (56 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 4.92
• Publications: 33 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 (MetaRNN=0.005666524).
• BP6: Variant 10-43111408-G-A is Benign according to our data. Variant chr10-43111408-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (159/152286) while in subpopulation EAS AF = 0.0275 (142/5164). AF 95% confidence interval is 0.0238. There are 2 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1465G>A	p.Asp489Asn	missense	Exon 7 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1465G>A	p.Asp489Asn	missense	Exon 7 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1465G>A	p.Asp489Asn	missense	Exon 7 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.1465G>A	p.Asp489Asn	missense	Exon 7 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1465G>A	p.Asp489Asn	missense	Exon 7 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1336G>A	p.Asp446Asn	missense	Exon 7 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152168 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00228 AC: 571 AN: 250940 AF XY: 0.00210

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00137 AC: 2000 AN: 1461432 Hom.: 56 Cov.: 57 AF XY: 0.00133 AC XY: 967 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000760 AC: 34 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0464 AC: 1844 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111946

Other (OTH) AF: 0.00147 AC: 89 AN: 60386

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152286 Hom.: 2 Cov.: 34 AF XY: 0.00106 AC XY: 79 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000718 AC: 11 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0275 AC: 142 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.00115

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Multiple endocrine neoplasia, type 2 (2)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	not provided (1)
-	-	1	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.81
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Benign	0.27	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.13
MVP		0.62
MPC		0.20
ClinPred		0.014	T
GERP RS		2.9
Varity_R		0.11
gMVP		0.56
Mutation Taster		=84/16	polymorphism

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: rs9282834; hg19: chr10-43606856; COSMIC: COSV60695200; COSMIC: COSV60695200;