rs2565206

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.74-126G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,104,434 control chromosomes in the GnomAD database, including 65,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 12401 hom., cov: 33)

Exomes 𝑓: 0.33 ( 53340 hom. )

Consequence

RET
NM_020975.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0150

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=-0.87).

BP6

Variant 10-43100333-G-T is Benign according to our data. Variant chr10-43100333-G-T is described in ClinVar as Benign. ClinVar VariationId is 677050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 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.74-126G>T	intron	N/A	NP_066124.1	P07949-1
RET	NM_001406743.1		c.74-126G>T	intron	N/A	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.74-126G>T	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.74-126G>T	intron	N/A	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.74-126G>T	intron	N/A	ENSP00000344798.4	P07949-2
RET	ENST00000713926.1		c.74-126G>T	intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57777

AN:

151560

Hom.:

12369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.589

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.326

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.370

GnomAD4 exome

AF:

0.326

AC:

310614

AN:

952784

Hom.:

53340

AF XY:

0.321

AC XY:

157441

AN XY:

490342

show subpopulations

African (AFR)

AF:

0.601

AC:

13577

AN:

22584

American (AMR)

AF:

0.263

AC:

9517

AN:

36130

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

7333

AN:

22314

East Asian (EAS)

AF:

0.132

AC:

4588

AN:

34864

South Asian (SAS)

AF:

0.218

AC:

15260

AN:

70082

European-Finnish (FIN)

AF:

0.254

AC:

10354

AN:

40774

Middle Eastern (MID)

AF:

0.286

AC:

951

AN:

3326

European-Non Finnish (NFE)

AF:

0.345

AC:

234702

AN:

679366

Other (OTH)

AF:

0.331

AC:

14332

AN:

43344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

11066

22132

33197

44263

55329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6100

12200

18300

24400

30500

<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:

0.381

AC:

57854

AN:

151650

Hom.:

12401

Cov.:

AF XY:

0.371

AC XY:

27505

AN XY:

74102

show subpopulations

African (AFR)

AF:

0.590

AC:

24394

AN:

41364

American (AMR)

AF:

0.321

AC:

4892

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

1130

AN:

3464

East Asian (EAS)

AF:

0.112

AC:

576

AN:

5154

South Asian (SAS)

AF:

0.198

AC:

951

AN:

4806

European-Finnish (FIN)

AF:

0.234

AC:

2436

AN:

10392

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.330

AC:

22406

AN:

67910

Other (OTH)

AF:

0.367

AC:

769

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1746

3492

5237

6983

8729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<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:

0.286

Hom.:

1713

Bravo

AF:

0.398

Asia WGS

AF:

0.187

AC:

651

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Multiple endocrine neoplasia, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.3

(source)

DANN

Benign

0.46

PhyloP100

-0.015

PromoterAI

-0.0046

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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