10-43083331-A-C

Position:

• chr10-43083331-A-C

Variant summary

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

The NM_020975.6(RET):​c.73+6000A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,208 control chromosomes in the GnomAD database, including 46,717 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 0.78 (46717 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.73+6000A>C		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.73+6000A>C		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118178 AN: 152090 Hom.: 46660 Cov.: 34

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.777 AC: 118298 AN: 152208 Hom.: 46717 Cov.: 34 AF XY: 0.770 AC XY: 57282 AN XY: 74400

Gnomad4 AFR AF: 0.901

Gnomad4 AMR AF: 0.761

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.639

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.771

Alfa AF: 0.756 Hom.: 6746

Bravo AF: 0.794

Asia WGS AF: 0.644 AC: 2242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.4
DANN	Benign	0.44

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: rs2435362; hg19: chr10-43578779;