rs2435357

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-43086608-T-C
• chr10-43086608-T-A
• chr10-43086608-T-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_020975.6(RET):c.73+9277T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.789 (AC=120,154) in the gnomAD database across 152,304 control chromosomes, including 48,464 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.944. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency: Genomes: 𝑓 0.79 (48464 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign; risk factor criteria provided, multiple submitters, no conflicts B:3 O:3
• Conservation: PhyloP100: -1.19
• Publications: 102 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: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9442 — exceeds 5%% threshold (BA1 applied)

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>C		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.73+9277T>C		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.73+9277T>C		intron	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.73+9277T>C		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.73+9277T>C		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.73+9277T>C		intron	N/A	ENSP00000519223.1	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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.789	AC:120018	Hom:48396	AN:152186	Cov:34
GnomAD4 genome	AF: 0.789	AC:120154	Hom:48464	AN:152304	Cov:34
TOPMed (Bravo)	AF: 0.808	AC:213824	Hom:87835	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.783	AC:68694	Hom:27184	AN:87708	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.807	AC:1889	Hom:761	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.552	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.717	AC:215	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.652	AC:2268	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.528	AC:3821	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.722	AC:127	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.591	AC:72414	Hom:21372	AN:122576	Cov:
Turkish Variome	AF: 0.744	AC:1150	Hom:430	AN:1546	Cov:
UK10K	AF: 0.755	AC:5709	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.555	AC:4973	Hom:1401	AN:8960	Cov:

Showing 14 sources

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

ClinVar

ClinVar submissions

Significance: Benign; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple endocrine neoplasia, type 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	-	Aganglionic megacolon (1)
-	-	-	Hirschsprung disease, susceptibility to, 1 (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.53
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.60
GPN-Star LLR	N/A	3.4
GPN-Star score	N/A	-0.28
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.2

Showing 8 of 8 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.

Other links and lift over

dbSNP: rs2435357;

hg19: chr10-43582056;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar