rs151267865

Variant names:

• chr10-43100610-G-A
• rs151267865
• NM_020975.6:c.225G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43100610-G-A
• chr10-43100610-G-T
• chr10-43100610-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_020975.6(RET):​c.225G>A​(p.Thr75Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T75T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.394
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-43100610-G-A is Benign according to our data. Variant chr10-43100610-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184368.
• BP7: Synonymous conserved (PhyloP=0.394 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000479 (73/152308) while in subpopulation AFR AF = 0.00147 (61/41566). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.225G>A	p.Thr75Thr	synonymous	Exon 2 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.225G>A	p.Thr75Thr	synonymous	Exon 2 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.225G>A	p.Thr75Thr	synonymous	Exon 2 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.225G>A	p.Thr75Thr	synonymous	Exon 2 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.225G>A	p.Thr75Thr	synonymous	Exon 2 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.225G>A	p.Thr75Thr	synonymous	Exon 2 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250936 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461644 Hom.: 0 Cov.: 64 AF XY: 0.0000454 AC XY: 33 AN XY: 727124

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112000

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74490

African (AFR) AF: 0.00147 AC: 61 AN: 41566

American (AMR) AF: 0.000653 AC: 10 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000608

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.60
PhyloP100		0.39
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism

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: rs151267865; hg19: chr10-43596058; COSMIC: COSV60709507; COSMIC: COSV60709507;