rs76397662

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_020975.6(RET):c.341G>A(p.Arg114His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R114C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:11O:1

Conservation

PhyloP100: 2.48

Publications

39 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0531303).

BP6

Variant 10-43102345-G-A is Benign according to our data. Variant chr10-43102345-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13947.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 = 0.000387 (59/152356) while in subpopulation EAS AF = 0.01 (52/5186). AF 95% confidence interval is 0.00785. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.341G>A	p.Arg114His	missense	Exon 3 of 20	NP_066124.1	P07949-1
RET	NM_001406743.1		c.341G>A	p.Arg114His	missense	Exon 3 of 21	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.341G>A	p.Arg114His	missense	Exon 3 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.341G>A	p.Arg114His	missense	Exon 3 of 20	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.341G>A	p.Arg114His	missense	Exon 3 of 19	ENSP00000344798.4	P07949-2
RET	ENST00000615310.5	TSL:5	c.341G>A	p.Arg114His	missense	Exon 3 of 17	ENSP00000480088.2	A0A087WWB1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000787

AC:

197

AN:

250370

AF XY:

0.000702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461580

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00680

AC:

270

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1112008

Other (OTH)

AF:

0.000248

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

111

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:

0.000387

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0100

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000241

Hom.:

Bravo

AF:

0.000363

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Multiple endocrine neoplasia, type 2 (2)

Congenital central hypoventilation (1)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia (1)

Multiple endocrine neoplasia type 2B (1)

not provided (1)

not specified (2)

Pheochromocytoma (1)

Renal hypodysplasia/aplasia 1 (1)

RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.40

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.80

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

PhyloP100

2.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.42

Sift

Benign

0.12

Sift4G

Uncertain

0.030

Polyphen

0.0010

Vest4

0.40

MVP

0.99

MPC

1.1

ClinPred

0.043

GERP RS

4.8

Varity_R

0.28

gMVP

0.58

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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