rs1896999

Variant names:

• chr10-43084144-T-C
• rs1896999
• NM_020975.6:c.73+6813T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020975.6(RET):​c.73+6813T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,180 control chromosomes in the GnomAD database, including 9,613 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 0.35 (9613 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 0 publications found

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]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.73+6813T>C		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.73+6813T>C		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.73+6813T>C		intron	N/A	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.73+6813T>C		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.73+6813T>C		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.73+6813T>C		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52762 AN: 152062 Hom.: 9595 Cov.: 34

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.347 AC: 52803 AN: 152180 Hom.: 9613 Cov.: 34 AF XY: 0.349 AC XY: 25973 AN XY: 74394

African (AFR) AF: 0.243 AC: 10087 AN: 41526

American (AMR) AF: 0.406 AC: 6208 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3472

East Asian (EAS) AF: 0.316 AC: 1637 AN: 5178

South Asian (SAS) AF: 0.420 AC: 2027 AN: 4826

European-Finnish (FIN) AF: 0.363 AC: 3836 AN: 10580

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26566 AN: 67988

Other (OTH) AF: 0.353 AC: 745 AN: 2112

Alfa AF: 0.355 Hom.: 1228

Bravo AF: 0.347

Asia WGS AF: 0.356 AC: 1236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.48
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1896999; hg19: chr10-43579592;