10-43099005-T-C

Position:

• chr10-43099005-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020975.6(RET):​c.74-1454T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,124 control chromosomes in the GnomAD database, including 47,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.79 (47969 hom., cov: 32)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.74-1454T>C		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.74-1454T>C		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119362 AN: 152004 Hom.: 47905 Cov.: 32

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.772

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.786 AC: 119495 AN: 152124 Hom.: 47969 Cov.: 32 AF XY: 0.778 AC XY: 57860 AN XY: 74354

Gnomad4 AFR AF: 0.949

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.708

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.772

Alfa AF: 0.746 Hom.: 5504

Bravo AF: 0.803

Asia WGS AF: 0.654 AC: 2277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.4
DANN	Benign	0.64

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: rs2505533; hg19: chr10-43594453;