rs75234356

Variant names:

• chr10-43120144-T-G
• rs75234356
• NM_020975.6:c.2671T>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM5 PP3 PP5_Very_Strong

The NM_020975.6(RET):​c.2671T>G​(p.Ser891Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,876 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004930755: Functional studies indicate this variant impacts protein function [PMID:25887804, 17209045, 16469774]." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S891L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 5.14
• Publications: 105 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: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004930755: Functional studies indicate this variant impacts protein function [PMID: 25887804, 17209045, 16469774].; SCV000290551: Experimental studies have shown that this missense change affects RET function (PMID: 10445857, 17209045, 26356818).; SCV000711449: "In vitro functional studies provide some evidence that the p.Ser891Ala variant may impact protein function (Iwashita 1999, Plaza Menacho 2005, Colombo 2015)."; SCV004838689: Functional studies have reported low to intermediate transforming activities and activation of kinase activity and downstream effectors (PMID: 10445857, 15753368, 25887804, 26356818).; SCV000329492: Published functional studies demonstrate a damaging effect: reduced transforming activity in vitro (Iwashita 1999, Colombo 2015); SCV000842757: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10445857, 15753368, 25887804); SCV000886054: Functional analyses of the variant protein show that it has low transforming activity (Colombo 2015, Iwashita 1999, Plaza Menacho 2005). PMID: 25887804. PMID: 10445857. PMID: 15753368.; SCV002774398: Functional studies indicate that this variant impacts protein function (PMIDs: 16469774 (2006), 26356818 (2015), 15753368 (2005)).; SCV004015164: Experimental studies have shown that this missense change increases the phosphorylation levels of downstream effectors such as Akt and STAT3, and has a moderate transforming activity in vitro (PMID: 10445857, 17209045, 26356818).; SCV001177214: Experimental studies have demonstrated that this alteration results in a moderate transforming activity in in vitro assays and increases phosphorylation levels of downstream effectors (Iwashita T et al. Oncogene. 1999 Jul;18:3919-22; Plaza-Menacho I et al. J Biol Chem. 2007 Mar;282:6415-24; Qi XP et al. Oncotarget. 2015 Oct;6:33993-4003).; SCV002051352: Several publications report experimental evidence evaluating an impact on protein function (example, Iwashita_1999, Plaza-Menacho_2007). The most pronounced variant effect results in increased transforming activity and constitutive kinase activity as monitored by RET phosphorylation and downstream phosphorylation of ERK 1/2.; SCV005339530: An in vitro study showed this variant results in low transforming activity and is associated with the development of familial medullary thyroid carcinoma (FMTC; Iwashita et al. 1999. PubMed ID: 10445857).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43120145-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3595005.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 10-43120144-T-G is Pathogenic according to our data. Variant chr10-43120144-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2671T>G	p.Ser891Ala	missense	Exon 15 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2671T>G	p.Ser891Ala	missense	Exon 15 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2671T>G	p.Ser891Ala	missense	Exon 15 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2671T>G	p.Ser891Ala	missense	Exon 15 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2671T>G	p.Ser891Ala	missense	Exon 15 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2407T>G	p.Ser803Ala	missense	Exon 15 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250656 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461682 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000118 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
4	-	-	Multiple endocrine neoplasia type 2A (4)
4	-	-	Multiple endocrine neoplasia, type 2 (4)
2	-	-	Familial medullary thyroid carcinoma (2)
2	-	-	Hirschsprung disease, susceptibility to, 1 (2)
2	-	-	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Medullary thyroid carcinoma;na:Multiple endocrine neoplasia II (1)
1	-	-	MEN2 phenotype: Unclassified (1)
1	-	-	Multiple endocrine neoplasia type 2B (1)
1	-	-	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.46	N
PhyloP100		5.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.73
Sift	Benign	0.11	T
Sift4G	Benign	0.31	T
Polyphen		0.97	D
Vest4		0.54
MVP		0.96
MPC		0.40
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.93
Mutation Taster		=4/96	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: rs75234356; hg19: chr10-43615592;