rs2435361

chr10-43083505-A-G

Variant summary

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

The NM_020975.6(RET):c.73+6174A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 152,168 control chromosomes in the GnomAD database, including 10,480 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 0.37 (10480 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310

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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.73+6174A>G		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.73+6174A>G		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55822 AN: 152050 Hom.: 10458 Cov.: 34

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.367 AC: 55869 AN: 152168 Hom.: 10480 Cov.: 34 AF XY: 0.369 AC XY: 27459 AN XY: 74380

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.370

Alfa AF: 0.371 Hom.: 1306

Bravo AF: 0.370

Asia WGS AF: 0.359 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	2.3
Dann	Benign	0.63

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: rs2435361; hg19: chr10-43578953;