4-54670209-T-G

Variant names:

• chr4-54670209-T-G
• rs2237028
• NM_000222.3:c.67+12128T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000222.3(KIT):​c.67+12128T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,038 control chromosomes in the GnomAD database, including 14,527 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14527 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.475 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.67+12128T>G		intron	N/A	NP_000213.1
	KIT	NM_001385284.1		c.67+12128T>G		intron	N/A	NP_001372213.1
	KIT	NM_001385290.1		c.67+12128T>G		intron	N/A	NP_001372219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.67+12128T>G		intron	N/A	ENSP00000288135.6
	KIT	ENST00000412167.7	TSL:1	c.67+12128T>G		intron	N/A	ENSP00000390987.3
	KIT	ENST00000687109.1		c.67+12128T>G		intron	N/A	ENSP00000509371.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65752 AN: 151918 Hom.: 14510 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.433 AC: 65800 AN: 152038 Hom.: 14527 Cov.: 32 AF XY: 0.429 AC XY: 31901 AN XY: 74304

African (AFR) AF: 0.481 AC: 19940 AN: 41454

American (AMR) AF: 0.470 AC: 7177 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1262 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5172

South Asian (SAS) AF: 0.297 AC: 1434 AN: 4822

European-Finnish (FIN) AF: 0.431 AC: 4559 AN: 10572

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28995 AN: 67966

Other (OTH) AF: 0.413 AC: 869 AN: 2106

Alfa AF: 0.427 Hom.: 37534

Bravo AF: 0.442

Asia WGS AF: 0.277 AC: 963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		0.024
Mutation Taster		=100/0	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: rs2237028; hg19: chr4-55536375;