chr10-43106497-G-A

Variant names:

• chr10-43106497-G-A
• rs80236571
• NM_020975.6:c.989G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_020975.6(RET):​c.989G>A​(p.Arg330Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 10-43106497-G-A is Pathogenic according to our data. Variant chr10-43106497-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13926.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr10-43106497-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.989G>A	p.Arg330Gln	missense_variant	Exon 5 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.989G>A	p.Arg330Gln	missense_variant	Exon 5 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:1 Uncertain:1

Feb 22, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported in patients affected with AD Hirschsprung disease. -

Apr 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 330 of the RET protein (p.Arg330Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant has been observed in individuals and families with Hirschsprung disase (PMID: 7633441, 8114939, 7581377). ClinVar contains an entry for this variant (Variation ID: 13926). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RET protein function (PMID: 8894691). -

Hirschsprung disease, susceptibility to, 1 Pathogenic:1 Other:1

Jan 27, 1994

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.989G>A(p.Arg330Gln) in RET gene has been reported previously in individuals with Hirschsprung disease (Pelet A, et al., 2005, Edery P, et al., 1994). Experimental studies have shown that this missense change affects RET function, however, available evidence is insufficient to prove pathogenicity (Iwashita T, 1996). This variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ risk factor. The amino acid Arg at position 330 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-Probably damaging, SIFT-Tolerated and MutationTaster-disease causing) predicts conflicting evidence on protein structure and function for this variant.The reference amino acid p.Arg330Gln in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Jul 07, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.99	N;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.24	T;.;T
Sift4G	Benign	0.61	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.61
MutPred		0.76		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.97
MPC		0.83
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80236571; hg19: chr10-43601945; COSMIC: COSV60691814; COSMIC: COSV60691814;