rs1554818959

Variant names:

• chr10-43114721-T-A
• rs1554818959
• NM_020975.6:c.2121T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43114721-T-A
• chr10-43114721-T-C
• chr10-43114721-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020975.6(RET):​c.2121T>A​(p.Asp707Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D707G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.402
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16838431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2121T>A	p.Asp707Glu	missense_variant	Exon 11 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2121T>A	p.Asp707Glu	missense_variant	Exon 11 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458786 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725732

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111794

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D707E variant (also known as c.2121T>A), located in coding exon 11 of the RET gene, results from a T to A substitution at nucleotide position 2121. The aspartic acid at codon 707 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was reported in multiple individuals diagnosed with medullary thyroid cancer with or without pheochromocytoma from a large Han Chinese family; however, this variant was not present in all affected individuals (Zhang L et al. Pathobiology. 2017 Nov;84:152-160). This alteration was also detected in numerous individuals with medullary thyroid cancer in a large, extended Chinese family; however, all individuals with this variant also had RET p.C634Y, a well-established pathogenic alteration associated with multiple endocrine neoplasia type 2 phenotype (Lu F et al. Oncol Lett. 2017 Sep;14:3552-3558; Kloos et al. Thyroid. 2009 Jun;19:565-612). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.39
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.1	L;L
PhyloP100		-0.40
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.11	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.73	P;P
Vest4		0.23
MutPred		0.26		Gain of disorder (P = 0.1216);Gain of disorder (P = 0.1216);
MVP		0.73
MPC		0.19
ClinPred		0.55	D
GERP RS		-8.8
Varity_R		0.40
gMVP		0.63
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs1554818959; hg19: chr10-43610169;