rs200375589

Variant names:

• chr4-54727442-G-A
• rs200375589
• NM_000222.3:c.1674G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-54727442-G-A
• chr4-54727442-G-C
• chr4-54727442-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000222.3(KIT):​c.1674G>A​(p.Lys558Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KIT NM_000222.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 1.48
• Publications: 22 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 4-54727442-G-A is Benign according to our data. Variant chr4-54727442-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220634.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000158 (24/152300) while in subpopulation NFE AF = 0.000235 (16/68026). AF 95% confidence interval is 0.000147. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 AD gene.

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.1674G>A	p.Lys558Lys	synonymous	Exon 11 of 21	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.1677G>A	p.Lys559Lys	synonymous	Exon 11 of 21	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.1677G>A	p.Lys559Lys	synonymous	Exon 11 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.1674G>A	p.Lys558Lys	synonymous	Exon 11 of 21	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.1665G>A	p.Lys555Lys	synonymous	Exon 11 of 21	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.1677G>A	p.Lys559Lys	synonymous	Exon 11 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250938 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000246

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: 0.0000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 78 AN XY: 727220

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111978

Other (OTH) AF: 0.0000662 AC: 4 AN: 60390

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74480

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

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

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.64
PhyloP100		1.5
Mutation Taster		=99/1	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: rs200375589; hg19: chr4-55593608; COSMIC: COSV55398121;