chr10-43100520-A-G

Variant names:

• chr10-43100520-A-G
• rs1800858
• NM_020975.6:c.135A>G
• RET p.Ala45Ala

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 -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_020975.6(RET):c.135A>G (p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.745 (AC=1,202,244) in the gnomAD database across 1,613,574 control chromosomes, including 451,003 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 (47935 hom., cov: 32)
  • Exomes 𝑓: 0.74 (403068 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.19
• Publications: 96 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 -17 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 submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (13/13 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	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.135A>G p.Ala45Ala	synonymous	Exon 2 of 20	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.135A>G p.Ala45Ala	synonymous	Exon 2 of 21	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.135A>G p.Ala45Ala	synonymous	Exon 2 of 20	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 20

synonymous

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 21

synonymous

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 20

synonymous

Prot: NP_001393673.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET ENST00000355710.8	TSL:5MANE Select	c.135A>G p.Ala45Ala	synonymous	Exon 2 of 20	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.135A>G p.Ala45Ala	synonymous	Exon 2 of 19	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000713926.1		c.135A>G p.Ala45Ala	synonymous	Exon 2 of 19	Prot: ENSP00000519223.1 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 20

synonymous

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 19

synonymous

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000713926.1

HGVSc / HGVSpc.135A>Gp.Ala45Ala

Exon rankExon 2 of 19

synonymous

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.785	AC:119303	Hom:47871	AN:151974	Cov:32
GnomAD2 exomes	AF: 0.731	AC:182618	Hom:	AN:249766	Cov:
GnomAD4 exome	AF: 0.741	AC:1082809	Hom:403068	AN:1461482	Cov:66
GnomAD4 genome	AF: 0.785	AC:119435	Hom:47935	AN:152092	Cov:32
TOPMed (Bravo)	AF: 0.803	AC:212579	Hom:86805	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.777	AC:96837	Hom:38077	AN:124678	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.804	AC:1882	Hom:755	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.557	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.720	AC:216	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.809	AC:10524	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.654	AC:2275	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.522	AC:3774	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.672	AC:1350	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.579	AC:71109	Hom:20624	AN:122716	Cov:
Turkish Variome	AF: 0.733	AC:4910	Hom:1808	AN:6698	Cov:
UK10K	AF: 0.750	AC:5668	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.564	AC:5050	Hom:1439	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.731 *	8111	11094	0.729 *	12812	17574
BipEx(Bipolar disorder (including schizoaffective))	0.737	20953	28420	0.739	21314	28844
Epi25(Epilepsy)	0.736	30895	41958	0.755	50506	66888
SCHEMA(Schizophrenia)	0.699	118698	169810	0.702	202130	287942

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple endocrine neoplasia, type 2 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia type 2A (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Pheochromocytoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.00027
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.024
DANN	Benign	0.31
GPN-Star LLR	N/A	3.3
GPN-Star score	N/A	-1.1
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	-2.2
PromoterAI	N/A	-0.0084	Neutral

Showing 9 of 9 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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1800858;

hg19: chr10-43595968;

COSMIC: COSV60686024;

COSMIC: COSV60686024;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar