10-43120057-G-A

Variant names:

• chr10-43120057-G-A
• rs2472737
• NM_020975.6:c.2608-24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000355710.8(RET):​c.2608-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,611,680 control chromosomes in the GnomAD database, including 39,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3284 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35940 hom.)
• Consequence: RET ENST00000355710.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.305
• Publications: 20 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-43120057-G-A is Benign according to our data. Variant chr10-43120057-G-A is described in ClinVar as Benign. ClinVar VariationId is 24956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355710.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2608-24G>A		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.2608-24G>A		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.2608-24G>A		intron	N/A	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2608-24G>A		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.2608-24G>A		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.2344-24G>A		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30780 AN: 152050 Hom.: 3272 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.204 AC: 50418 AN: 247006 AF XY: 0.204

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.219 AC: 319375 AN: 1459512 Hom.: 35940 Cov.: 37 AF XY: 0.217 AC XY: 157520 AN XY: 725856

African (AFR) AF: 0.141 AC: 4716 AN: 33430

American (AMR) AF: 0.156 AC: 6934 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3161 AN: 26072

East Asian (EAS) AF: 0.215 AC: 8518 AN: 39652

South Asian (SAS) AF: 0.162 AC: 13896 AN: 85872

European-Finnish (FIN) AF: 0.278 AC: 14788 AN: 53152

Middle Eastern (MID) AF: 0.178 AC: 969 AN: 5442

European-Non Finnish (NFE) AF: 0.228 AC: 253855 AN: 1111084

Other (OTH) AF: 0.208 AC: 12538 AN: 60292

GnomAD4 genome AF: 0.203 AC: 30818 AN: 152168 Hom.: 3284 Cov.: 33 AF XY: 0.206 AC XY: 15282 AN XY: 74364

African (AFR) AF: 0.150 AC: 6229 AN: 41542

American (AMR) AF: 0.193 AC: 2955 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1190 AN: 5158

South Asian (SAS) AF: 0.158 AC: 760 AN: 4820

European-Finnish (FIN) AF: 0.293 AC: 3103 AN: 10578

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15462 AN: 67982

Other (OTH) AF: 0.198 AC: 419 AN: 2114

Alfa AF: 0.209 Hom.: 5364

Bravo AF: 0.193

Asia WGS AF: 0.187 AC: 653 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.74
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs2472737; hg19: chr10-43615505; COSMIC: COSV60686346;