10-43100707-A-C

Variant names:

• chr10-43100707-A-C
• rs567877611
• NM_020975.6:c.322A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020975.6(RET):​c.322A>C​(p.Lys108Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,602,950 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K108N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (2 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.290
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009234339).
• BP6: Variant 10-43100707-A-C is Benign according to our data. Variant chr10-43100707-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477370.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000394 (6/152314) while in subpopulation SAS AF = 0.00104 (5/4820). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.322A>C	p.Lys108Gln	missense	Exon 2 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.322A>C	p.Lys108Gln	missense	Exon 2 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.322A>C	p.Lys108Gln	missense	Exon 2 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.322A>C	p.Lys108Gln	missense	Exon 2 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.322A>C	p.Lys108Gln	missense	Exon 2 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.322A>C	p.Lys108Gln	missense	Exon 2 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000186 AC: 42 AN: 225474 AF XY: 0.000204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000100 AC: 145 AN: 1450636 Hom.: 2 Cov.: 64 AF XY: 0.000142 AC XY: 102 AN XY: 720616

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 43360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.00161 AC: 136 AN: 84636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107048

Other (OTH) AF: 0.0000334 AC: 2 AN: 59920

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000190 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Multiple endocrine neoplasia, type 2 (1)
-	1	-	not provided (1)
-	-	1	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.62
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.38	N
PhyloP100		0.29
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.13
Sift	Benign	0.75	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.27		Loss of ubiquitination at K108 (P = 0.0148)
MVP		0.45
MPC		0.81
ClinPred		0.0061	T
GERP RS		0.17
PromoterAI		-0.0010	Neutral
Varity_R		0.12
gMVP		0.45
Mutation Taster		=86/14	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: rs567877611; hg19: chr10-43596155; COSMIC: COSV105901448;