10-43077059-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The 10-43077059-A-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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.336

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]

ACMG classification

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/exons	MANE	UniProt
RET	NM_020975.6			upstream_gene_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8			upstream_gene_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116140 AN: 151032 Hom.: 45207 Cov.: 31

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.: 7 AF XY: 0.749 AC XY: 183227 AN XY: 244788

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.: 31 AF XY: 0.763 AC XY: 56329 AN XY: 73848

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Multiple endocrine neoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hirschsprung Disease, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Other links and lift over

dbSNP: rs10900296; hg19: chr10-43572507;