chr10-43086608-T-A

Variant names:

• chr10-43086608-T-A
• rs2435357
• NM_020975.6:c.73+9277T>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_020975.6(RET):c.73+9277T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 17 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000122 by highest known P/LP ClinVar AF 0.000122) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET NM_020975.6	MANE Select	c.73+9277T>A	intron	Intron 1 of 19	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.73+9277T>A	intron	Intron 1 of 20	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.73+9277T>A	intron	Intron 1 of 19	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 19

intron

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 20

intron

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 19

intron

Prot: NP_001393673.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET ENST00000355710.8	TSL:5MANE Select	c.73+9277T>A	intron	Intron 1 of 19	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.73+9277T>A	intron	Intron 1 of 18	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000713926.1		c.73+9277T>A	intron	Intron 1 of 18	Prot: ENSP00000519223.1 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 19

intron

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 18

intron

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000713926.1

HGVSc / HGVSpc.73+9277T>A

Exon rankIntron 1 of 18

intron

Prot: ENSP00000519223.1UniProt: A0AAQ5BH28

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:34

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.50
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.37
DANN	Benign	0.72
GPN-Star LLR	N/A	0.20
GPN-Star score	N/A	-0.20
PhyloP100	Benign	-1.2

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Saturation mutagenesis MPRA of RET enhancer

• Gene: RET enhancer
• Score: 0.0300

No calibration data

This score is at approximately the 70th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs2435357;

hg19: chr10-43582056;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar