rs2435351

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020975.6(RET):c.337+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,583,280 control chromosomes in the GnomAD database, including 52,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3868 hom., cov: 31)

Exomes 𝑓: 0.25 ( 48375 hom. )

Consequence

RET
NM_020975.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.12

Publications

15 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 10-43100731-G-A is Benign according to our data. Variant chr10-43100731-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.279 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RET	NM_020975.6	MANE Select	c.337+9G>A	intron	N/A	NP_066124.1	P07949-1
RET	NM_001406743.1		c.337+9G>A	intron	N/A	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.337+9G>A	intron	N/A	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RET	ENST00000355710.8	TSL:5 MANE Select	c.337+9G>A	intron	N/A	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.337+9G>A	intron	N/A	ENSP00000344798.4	P07949-2
RET	ENST00000713926.1		c.337+9G>A	intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31729

AN:

151540

Hom.:

3864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0949

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.260

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.212

GnomAD2 exomes

AF:

0.257

AC:

50491

AN:

196552

AF XY:

0.258

show subpopulations

Gnomad AFR exome

AF:

0.0954

Gnomad AMR exome

AF:

0.356

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.255

AC:

364788

AN:

1431622

Hom.:

48375

Cov.:

AF XY:

0.256

AC XY:

181424

AN XY:

709260

show subpopulations

African (AFR)

AF:

0.0896

AC:

2961

AN:

33062

American (AMR)

AF:

0.342

AC:

13831

AN:

40452

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6283

AN:

25512

East Asian (EAS)

AF:

0.0886

AC:

3417

AN:

38576

South Asian (SAS)

AF:

0.302

AC:

24967

AN:

82536

European-Finnish (FIN)

AF:

0.255

AC:

12687

AN:

49806

Middle Eastern (MID)

AF:

0.276

AC:

1314

AN:

4766

European-Non Finnish (NFE)

AF:

0.260

AC:

285060

AN:

1097762

Other (OTH)

AF:

0.241

AC:

14268

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14805

29610

44416

59221

74026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9594

19188

28782

38376

47970

<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:

0.209

AC:

31738

AN:

151658

Hom.:

3868

Cov.:

AF XY:

0.212

AC XY:

15735

AN XY:

74094

show subpopulations

African (AFR)

AF:

0.0947

AC:

3922

AN:

41422

American (AMR)

AF:

0.260

AC:

3962

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

853

AN:

3470

East Asian (EAS)

AF:

0.101

AC:

519

AN:

5164

South Asian (SAS)

AF:

0.292

AC:

1402

AN:

4808

European-Finnish (FIN)

AF:

0.258

AC:

2687

AN:

10412

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.259

AC:

17561

AN:

67862

Other (OTH)

AF:

0.210

AC:

440

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1169

2338

3507

4676

5845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.234

Hom.:

2329

Bravo

AF:

0.207

Asia WGS

AF:

0.182

AC:

631

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Pheochromocytoma (2)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia (1)

Multiple endocrine neoplasia type 2A (1)

Multiple endocrine neoplasia type 2B (1)

Multiple endocrine neoplasia, type 2 (1)

Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.1

PromoterAI

0.053

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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