10-43128364-C-T

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.*95C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,457,726 control chromosomes in the GnomAD database, including 32,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2708 hom., cov: 32)

Exomes 𝑓: 0.21 ( 29710 hom. )

Consequence

RET
NM_020975.6 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.303

Publications

25 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=-0.46).

BP6

Variant 10-43128364-C-T is Benign according to our data. Variant chr10-43128364-C-T is described in ClinVar as Benign. ClinVar VariationId is 299903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 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.*95C>T	3_prime_UTR	Exon 20 of 20	NP_066124.1
RET	NM_001406759.1		c.*95C>T	3_prime_UTR	Exon 20 of 20	NP_001393688.1
RET	NM_020630.7		c.*1610C>T	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.*95C>T	3_prime_UTR	Exon 20 of 20	ENSP00000347942.3
RET	ENST00000683007.1		n.4403C>T	non_coding_transcript_exon	Exon 16 of 16
RET	ENST00000615310.5	TSL:5	c.*1610C>T	3_prime_UTR	Exon 17 of 17	ENSP00000480088.2

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25539

AN:

151992

Hom.:

2699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0415

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.294

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.167

GnomAD4 exome

AF:

0.208

AC:

271591

AN:

1305616

Hom.:

29710

Cov.:

AF XY:

0.207

AC XY:

135766

AN XY:

657000

show subpopulations

African (AFR)

AF:

0.0332

AC:

1006

AN:

30302

American (AMR)

AF:

0.147

AC:

6428

AN:

43704

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

4288

AN:

25170

East Asian (EAS)

AF:

0.215

AC:

8307

AN:

38682

South Asian (SAS)

AF:

0.148

AC:

12235

AN:

82542

European-Finnish (FIN)

AF:

0.277

AC:

13470

AN:

48658

Middle Eastern (MID)

AF:

0.147

AC:

808

AN:

5498

European-Non Finnish (NFE)

AF:

0.220

AC:

214224

AN:

975750

Other (OTH)

AF:

0.196

AC:

10825

AN:

55310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

11258

22516

33774

45032

56290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6828

13656

20484

27312

34140

<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:

0.168

AC:

25560

AN:

152110

Hom.:

2708

Cov.:

AF XY:

0.174

AC XY:

12914

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0414

AC:

1717

AN:

41506

American (AMR)

AF:

0.175

AC:

2672

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

620

AN:

3470

East Asian (EAS)

AF:

0.231

AC:

1196

AN:

5174

South Asian (SAS)

AF:

0.144

AC:

695

AN:

4810

European-Finnish (FIN)

AF:

0.294

AC:

3101

AN:

10548

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.220

AC:

14936

AN:

67990

Other (OTH)

AF:

0.174

AC:

367

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1060

2120

3181

4241

5301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.195

Hom.:

5388

Bravo

AF:

0.153

Asia WGS

AF:

0.177

AC:

615

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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.

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

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Multiple endocrine neoplasia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Jul 10, 2025

GeneKor MSA

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

-0.46

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.30

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