NM_020975.6:c.2137-324A>G

Variant names:

• chr10-43116260-A-G
• rs741968
• NM_020975.6:c.2137-324A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020975.6(RET):​c.2137-324A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 152,252 control chromosomes in the GnomAD database, including 53,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.83 (53041 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.27
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 10-43116260-A-G is Benign according to our data. Variant chr10-43116260-A-G is described in ClinVar as Benign. ClinVar VariationId is 1267407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

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.2137-324A>G		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2137-324A>G		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2137-324A>G		intron	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2137-324A>G		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2137-324A>G		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1873-324A>G		intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.830 AC: 126289 AN: 152134 Hom.: 52977 Cov.: 34

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.820

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.830 AC: 126417 AN: 152252 Hom.: 53041 Cov.: 34 AF XY: 0.827 AC XY: 61580 AN XY: 74434

African (AFR) AF: 0.914 AC: 37971 AN: 41550

American (AMR) AF: 0.805 AC: 12318 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2666 AN: 3470

East Asian (EAS) AF: 0.497 AC: 2565 AN: 5166

South Asian (SAS) AF: 0.713 AC: 3440 AN: 4826

European-Finnish (FIN) AF: 0.822 AC: 8719 AN: 10612

Middle Eastern (MID) AF: 0.791 AC: 231 AN: 292

European-Non Finnish (NFE) AF: 0.823 AC: 55938 AN: 68004

Other (OTH) AF: 0.819 AC: 1730 AN: 2112

Alfa AF: 0.820 Hom.: 10391

Bravo AF: 0.836

Asia WGS AF: 0.626 AC: 2179 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.31
PhyloP100		-2.3
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: rs741968; hg19: chr10-43611708;