10-43085325-G-C

Position:

• chr10-43085325-G-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+7994G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,130 control chromosomes in the GnomAD database, including 12,046 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 0.40 (12046 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.860

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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.73+7994G>C		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.73+7994G>C		intron_variant		5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60095 AN: 152012 Hom.: 12022 Cov.: 33

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.395 AC: 60164 AN: 152130 Hom.: 12046 Cov.: 33 AF XY: 0.395 AC XY: 29367 AN XY: 74358

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.392

Alfa AF: 0.238 Hom.: 528

Bravo AF: 0.403

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.66

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: rs2506007; hg19: chr10-43580773;