chr10-43129385-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_020975.6(RET):c.*1116T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 233,622 control chromosomes in the GnomAD database, including 5,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3845 hom., cov: 32)

Exomes 𝑓: 0.22 ( 2067 hom. )

Consequence

RET
NM_020975.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.835

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: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 10-43129385-T-C is Benign according to our data. Variant chr10-43129385-T-C is described in ClinVar as Benign. ClinVar VariationId is 299925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 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
RET	NM_020975.6	MANE Select	c.*1116T>C	3_prime_UTR	Exon 20 of 20	NP_066124.1
RET	NM_001406759.1		c.*1116T>C	3_prime_UTR	Exon 20 of 20	NP_001393688.1
RET	NM_020630.7		c.*2631T>C	3_prime_UTR	Exon 19 of 19	NP_065681.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RET	ENST00000355710.8	TSL:5 MANE Select	c.*1116T>C	3_prime_UTR	Exon 20 of 20	ENSP00000347942.3
RET	ENST00000683007.1		n.5424T>C	non_coding_transcript_exon	Exon 16 of 16
RET	ENST00000615310.5	TSL:5	c.*2631T>C	3_prime_UTR	Exon 17 of 17	ENSP00000480088.2

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33459

AN:

152100

Hom.:

3833

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.218

GnomAD4 exome

AF:

0.224

AC:

18221

AN:

81404

Hom.:

2067

Cov.:

AF XY:

0.225

AC XY:

8440

AN XY:

37474

show subpopulations

African (AFR)

AF:

0.155

AC:

603

AN:

3898

American (AMR)

AF:

0.182

AC:

454

AN:

2496

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

928

AN:

5124

East Asian (EAS)

AF:

0.196

AC:

2237

AN:

11412

South Asian (SAS)

AF:

0.174

AC:

122

AN:

702

European-Finnish (FIN)

AF:

0.294

AC:

143

AN:

486

Middle Eastern (MID)

AF:

0.203

AC:

100

AN:

492

European-Non Finnish (NFE)

AF:

0.243

AC:

12141

AN:

50020

Other (OTH)

AF:

0.220

AC:

1493

AN:

6774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

831

1663

2494

3326

4157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.220

AC:

33501

AN:

152218

Hom.:

3845

Cov.:

AF XY:

0.223

AC XY:

16609

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.167

AC:

6926

AN:

41524

American (AMR)

AF:

0.215

AC:

3283

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

664

AN:

3468

East Asian (EAS)

AF:

0.231

AC:

1199

AN:

5186

South Asian (SAS)

AF:

0.164

AC:

793

AN:

4832

European-Finnish (FIN)

AF:

0.305

AC:

3232

AN:

10588

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.245

AC:

16640

AN:

68004

Other (OTH)

AF:

0.224

AC:

474

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1348

2696

4043

5391

6739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.230

Hom.:

14613

Bravo

AF:

0.211

Asia WGS

AF:

0.194

AC:

676

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Pheochromocytoma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Hirschsprung disease, susceptibility to, 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Renal hypodysplasia/aplasia 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Multiple endocrine neoplasia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.83

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over