chr10-43077063-C-A

Variant names:

• chr10-43077063-C-A
• rs10900297
• ENST00000935252.1:c.-196C>A

Variant summary

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

The ENST00000935252.1(RET):​c.-196C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 744,828 control chromosomes in the GnomAD database, including 55,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13195 hom., cov: 33)
  • Exomes 𝑓: 0.36 (42770 hom.)
• Consequence: RET ENST00000935252.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.315
• Publications: 22 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

ENSG00000303432 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-43077063-C-A is Benign according to our data. Variant chr10-43077063-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000935252.1. 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.-196C>A		upstream_gene	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.-196C>A		upstream_gene	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.-196C>A		upstream_gene	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000935252.1		c.-196C>A		5_prime_UTR	Exon 1 of 15	ENSP00000605311.1
	ENSG00000303432	ENST00000794440.1		n.49G>T		splice_region non_coding_transcript_exon	Exon 1 of 3
	ENSG00000303432	ENST00000794441.1		n.86G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62655 AN: 151278 Hom.: 13165 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.388

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.362 AC: 215063 AN: 593442 Hom.: 42770 Cov.: 8 AF XY: 0.363 AC XY: 104807 AN XY: 288616

African (AFR) AF: 0.456 AC: 5622 AN: 12324

American (AMR) AF: 0.425 AC: 2533 AN: 5960

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 3290 AN: 10298

East Asian (EAS) AF: 0.264 AC: 5638 AN: 21344

South Asian (SAS) AF: 0.420 AC: 6774 AN: 16116

European-Finnish (FIN) AF: 0.360 AC: 6436 AN: 17880

Middle Eastern (MID) AF: 0.407 AC: 733 AN: 1802

European-Non Finnish (NFE) AF: 0.362 AC: 174297 AN: 481366

Other (OTH) AF: 0.370 AC: 9740 AN: 26352

GnomAD4 genome AF: 0.414 AC: 62733 AN: 151386 Hom.: 13195 Cov.: 33 AF XY: 0.415 AC XY: 30709 AN XY: 74058

African (AFR) AF: 0.476 AC: 19687 AN: 41330

American (AMR) AF: 0.434 AC: 6613 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1136 AN: 3464

East Asian (EAS) AF: 0.316 AC: 1616 AN: 5120

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4816

European-Finnish (FIN) AF: 0.362 AC: 3775 AN: 10420

Middle Eastern (MID) AF: 0.403 AC: 117 AN: 290

European-Non Finnish (NFE) AF: 0.391 AC: 26494 AN: 67706

Other (OTH) AF: 0.406 AC: 856 AN: 2106

Alfa AF: 0.398 Hom.: 1474

Bravo AF: 0.424

Asia WGS AF: 0.360 AC: 1217 AN: 3384

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hirschsprung Disease, Dominant (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.68
PhyloP100		-0.32
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	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: rs10900297; hg19: chr10-43572511;