dbSNP rs79658334: RET:p.Val804Met (chr10-43119548-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PM5PP3_ModeratePP5_Very_Strong

The NM_020975.6(RET):c.2410G>A(p.Val804Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,605,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000290546: Experimental studies have shown that this missense change affects RET function (PMID:15184865, 20039896, 21711375)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V804A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:47

Conservation

PhyloP100: 9.99

Publications

467 publications found

Variant links:

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

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000290546: Experimental studies have shown that this missense change affects RET function (PMID: 15184865, 20039896, 21711375).; SCV000711346: "In vitro functional studies provide some evidence that this variant may impact protein function (Machens 2011, Castellone 2010)."; SCV004357247: Functional studies have reported that the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865).; SCV004822637: Functional studies have reported that the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865).; SCV000234936: Published functional studies demonstrate a damaging effect: increased transforming activity (Cosci et al., 2011); SCV000605023: Additionally, in vitro functional studies demonstrate increased cellular proliferation and tyrosine kinase activity, as well as a conferred resistance to selective kinase inhibitors (Carlomagno 2004, Castellone 2010, Cosci 2011, Machens 2011).; SCV002069070: Experimental studies have shown that this pathogenic sequence change affects the normal function of the RET protein (PMID: 20039896 21711375).; SCV002774396: Increased kinase activity, altered substrate specificity, and resistance to some drugs have been observed in the published literature (PMID: 21454698 (2011)).; SCV002817215: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21454698); SCV000674764: "In vitro analyses demonstrated that cells transfected with the p.V804M alteration produced an intermediate number of focus formation units and an intermediate number of colonies when compared to wild-type, but did not show any significant difference from wild-type with respect to the proliferation rate (Cosci, 2011). Additional in vitro analysis shows that the RET p.V804M alteration has a marked increase in kinase activity over wild-type (Machens, 2011)."; SCV000821780: Moreover, this prediction has been confirmed experimentally (PMID: 20039896,21711375,) .; SCV000840056: In vitro analysis showed that this variant affect the function of the RET protein [PMID 21810974].; SCV004043759: Functional studies indicate this variant impacts protein function [PMID: 24560924, 21810974, 21711375, 20039896, 15184865].; SCV000699459: "These studies showed the variant moderately increased transforming activity (Cosci_2011) and increased kinase activity compared to WT (Plaza-Menacho_2011)."; SCV003927229: In vitro functional studies demonstrate this substitution leads to increased cellular proliferation and increased tyrosine kinase activity. This is supported by structural analysis that indicates the alteration changes the conformation of the ATP binding pocket, making it more permissive for binding ATP, and thus enhancing RET activation.; SCV004239131: Experimental studies have shown that this missense change affects RET function (PMID: 15184865, 20039896, 21711375).; SCV000807027: Functional studies show the p.Val804Met variant results in slightly higher growth and transformation rates compared to wild type RET (Cosci et al. 2011. PubMed ID: 21810974).; SCV005900689: Functional in vitro studies showed that this variant had an effect on RET protein function (PMID: 21810974, 21711375, 20039896).; SCV005416796: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-43119548-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 10-43119548-G-A is Pathogenic according to our data. Variant chr10-43119548-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	NM_020975.6	MANE Select	c.2410G>A	p.Val804Met	missense	Exon 14 of 20	NP_066124.1	P07949-1
RET	NM_001406743.1		c.2410G>A	p.Val804Met	missense	Exon 14 of 21	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.2410G>A	p.Val804Met	missense	Exon 14 of 20	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	ENST00000355710.8	TSL:5 MANE Select	c.2410G>A	p.Val804Met	missense	Exon 14 of 20	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.2410G>A	p.Val804Met	missense	Exon 14 of 19	ENSP00000344798.4	P07949-2
RET	ENST00000713926.1		c.2146G>A	p.Val716Met	missense	Exon 14 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000125

AC:

AN:

232600

AF XY:

0.000149

show subpopulations

Gnomad AFR exome

AF:

0.0000710

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000567

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

181

AN:

1453366

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

722824

show subpopulations

African (AFR)

AF:

0.0000902

AC:

AN:

33274

American (AMR)

AF:

0.000226

AC:

AN:

44158

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25994

East Asian (EAS)

AF:

0.000127

AC:

AN:

39396

South Asian (SAS)

AF:

0.000140

AC:

AN:

85494

European-Finnish (FIN)

AF:

0.000139

AC:

AN:

50314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.000121

AC:

134

AN:

1109962

Other (OTH)

AF:

0.000150

AC:

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000116

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (14)

Multiple endocrine neoplasia type 2A (7)

Multiple endocrine neoplasia, type 2 (7)

Hereditary cancer-predisposing syndrome (5)

Familial medullary thyroid carcinoma (4)

RET-related disorder (3)

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (2)

Hirschsprung disease, susceptibility to, 1 (1)

Inherited phaeochromocytoma and paraganglioma excluding NF1 (1)

MEN2 phenotype: Unclassified (1)

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1619700:Renal hypodysplasia/aplasia 1;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

-0.91

PhyloP100

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.72

Sift

Uncertain

0.021

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.90

MVP

0.90

MPC

0.78

ClinPred

0.14

GERP RS

5.4

Varity_R

0.77

gMVP

0.79

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over