Genetic Variant RET:c.-200A>G (chr10-43077059-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020975.6(RET):c.-200A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 652,438 control chromosomes in the GnomAD database, including 186,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45255 hom., cov: 31)

Exomes 𝑓: 0.75 ( 141070 hom. )

Consequence

RET
NM_020975.6 upstream_gene

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.336

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 10-43077059-A-G is Benign according to our data. Variant chr10-43077059-A-G is described in ClinVar as [Benign]. Clinvar id is 368898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.-200A>G		upstream_gene_variant		ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.-200A>G		upstream_gene_variant		5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116140

AN:

151032

Hom.:

45207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.871

Gnomad AMI

AF:

0.834

Gnomad AMR

AF:

0.756

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.537

Gnomad SAS

AF:

0.713

Gnomad FIN

AF:

0.643

Gnomad MID

AF:

0.705

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.761

GnomAD4 exome

AF:

0.749

AC:

375266

AN:

501298

Hom.:

141070

Cov.:

AF XY:

0.749

AC XY:

183227

AN XY:

244788

show subpopulations

Gnomad4 AFR exome

AF:

0.877

Gnomad4 AMR exome

AF:

0.751

Gnomad4 ASJ exome

AF:

0.717

Gnomad4 EAS exome

AF:

0.600

Gnomad4 SAS exome

AF:

0.724

Gnomad4 FIN exome

AF:

0.682

Gnomad4 NFE exome

AF:

0.757

Gnomad4 OTH exome

AF:

0.746

GnomAD4 genome

AF:

0.769

AC:

116250

AN:

151140

Hom.:

45255

Cov.:

AF XY:

0.763

AC XY:

56329

AN XY:

73848

show subpopulations

Gnomad4 AFR

AF:

0.871

Gnomad4 AMR

AF:

0.757

Gnomad4 ASJ

AF:

0.701

Gnomad4 EAS

AF:

0.538

Gnomad4 SAS

AF:

0.714

Gnomad4 FIN

AF:

0.643

Gnomad4 NFE

AF:

0.753

Gnomad4 OTH

AF:

0.760

Alfa

AF:

0.669

Hom.:

2129

Bravo

AF:

0.784

Asia WGS

AF:

0.635

AC:

2138

AN:

3368

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypodysplasia/aplasia 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hirschsprung Disease, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.5

DANN

Benign

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over