10-43111202-C-T

Variant names:

• chr10-43111202-C-T
• rs9282835
• NM_020975.6:c.1264-5C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020975.6(RET):​c.1264-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,613,594 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (226 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (199 hom.)
• Consequence: RET NM_020975.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002790
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.117
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-43111202-C-T is Benign according to our data. Variant chr10-43111202-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0966 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.1264-5C>T		splice_region intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1264-5C>T		splice_region intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1264-5C>T		splice_region 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.1264-5C>T		splice_region intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1264-5C>T		splice_region intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1135-5C>T		splice_region intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4480 AN: 152146 Hom.: 227 Cov.: 32

Gnomad AFR AF: 0.0992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00855 AC: 2138 AN: 250094 AF XY: 0.00637

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00975

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00359 AC: 5243 AN: 1461330 Hom.: 199 Cov.: 31 AF XY: 0.00319 AC XY: 2316 AN XY: 726988

African (AFR) AF: 0.0999 AC: 3344 AN: 33480

American (AMR) AF: 0.00970 AC: 434 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26132

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

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86244

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53000

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.000747 AC: 831 AN: 1111906

Other (OTH) AF: 0.00873 AC: 527 AN: 60380

GnomAD4 genome AF: 0.0295 AC: 4488 AN: 152264 Hom.: 226 Cov.: 32 AF XY: 0.0275 AC XY: 2050 AN XY: 74444

African (AFR) AF: 0.0991 AC: 4116 AN: 41534

American (AMR) AF: 0.0169 AC: 258 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68010

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0146 Hom.: 188

Bravo AF: 0.0345

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Multiple endocrine neoplasia type 2A (2)
-	-	2	Multiple endocrine neoplasia type 2B (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;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.5
DANN	Benign	0.85
PhyloP100		0.12
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs9282835; hg19: chr10-43606650; COSMIC: COSV60687792;