4-54736599-G-C

Variant names:

• chr4-54736599-G-C
• rs3733542
• NM_000222.3:c.2586G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000222.3(KIT):​c.2586G>C​(p.Leu862Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,611,542 control chromosomes in the GnomAD database, including 14,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L862L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2832 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11200 hom.)
• Consequence: KIT NM_000222.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.635
• Publications: 52 publications found

Genes affected

KIT (HGNC:6342): (KIT proto-oncogene, receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration and function. This protein can be a membrane-bound or soluble protein. Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2020]

KIT Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cutaneous mastocytosis

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mastocytosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 4-54736599-G-C is Benign according to our data. Variant chr4-54736599-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.635 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000222.3. 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
	KIT	NM_000222.3	MANE Select	c.2586G>C	p.Leu862Leu	synonymous	Exon 18 of 21	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.2589G>C	p.Leu863Leu	synonymous	Exon 18 of 21	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.2586G>C	p.Leu862Leu	synonymous	Exon 18 of 21	NP_001372219.1	A0A8I5QKP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.2586G>C	p.Leu862Leu	synonymous	Exon 18 of 21	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.2574G>C	p.Leu858Leu	synonymous	Exon 18 of 21	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.2589G>C	p.Leu863Leu	synonymous	Exon 18 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24631 AN: 152060 Hom.: 2831 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0952

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.108 AC: 27099 AN: 251368 AF XY: 0.106

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.0620

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0517

Gnomad FIN exome AF: 0.0531

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.115 AC: 168537 AN: 1459364 Hom.: 11200 Cov.: 31 AF XY: 0.115 AC XY: 83171 AN XY: 726196

African (AFR) AF: 0.341 AC: 11375 AN: 33384

American (AMR) AF: 0.0661 AC: 2956 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2732 AN: 26128

East Asian (EAS) AF: 0.0517 AC: 2051 AN: 39688

South Asian (SAS) AF: 0.106 AC: 9115 AN: 86218

European-Finnish (FIN) AF: 0.0576 AC: 3075 AN: 53414

Middle Eastern (MID) AF: 0.100 AC: 576 AN: 5762

European-Non Finnish (NFE) AF: 0.116 AC: 129242 AN: 1109738

Other (OTH) AF: 0.123 AC: 7415 AN: 60318

GnomAD4 genome AF: 0.162 AC: 24666 AN: 152178 Hom.: 2832 Cov.: 32 AF XY: 0.154 AC XY: 11473 AN XY: 74402

African (AFR) AF: 0.329 AC: 13639 AN: 41474

American (AMR) AF: 0.0950 AC: 1453 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0985 AC: 342 AN: 3472

East Asian (EAS) AF: 0.0551 AC: 285 AN: 5174

South Asian (SAS) AF: 0.105 AC: 505 AN: 4832

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10608

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7533 AN: 68006

Other (OTH) AF: 0.139 AC: 295 AN: 2116

Alfa AF: 0.122 Hom.: 476

Bravo AF: 0.174

Asia WGS AF: 0.106 AC: 372 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Gastrointestinal stromal tumor (3)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Mastocytosis (1)
-	-	1	not specified (1)
-	-	1	Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.3
DANN	Benign	0.47
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3733542; hg19: chr4-55602765; COSMIC: COSV55388515; COSMIC: COSV55388515;