rs373540097

Variant names:

• chr10-43109125-G-A
• rs373540097
• NM_020975.6:c.1158G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43109125-G-A
• chr10-43109125-G-C
• chr10-43109125-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_020975.6(RET):​c.1158G>A​(p.Ala386Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,752 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. A386A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.252
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-43109125-G-A is Benign according to our data. Variant chr10-43109125-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136095.
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.

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.1158G>A	p.Ala386Ala	synonymous	Exon 6 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1158G>A	p.Ala386Ala	synonymous	Exon 6 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1158G>A	p.Ala386Ala	synonymous	Exon 6 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.1158G>A	p.Ala386Ala	synonymous	Exon 6 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1158G>A	p.Ala386Ala	synonymous	Exon 6 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1029G>A	p.Ala343Ala	synonymous	Exon 6 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 250982 AF XY: 0.000420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1461598 Hom.: 0 Cov.: 33 AF XY: 0.000250 AC XY: 182 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 206 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1112006

Other (OTH) AF: 0.000596 AC: 36 AN: 60392

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41424

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000298

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.7
DANN	Benign	0.66
PhyloP100		0.25
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: rs373540097; hg19: chr10-43604573;