chr4-54671315-C-G

Variant names:

• chr4-54671315-C-G
• rs759083
• NM_000222.3:c.67+13234C>G

Variant summary

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

The NM_001385284.1(KIT):​c.67+13234C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 151,930 control chromosomes in the GnomAD database, including 7,853 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 0.31 (7853 hom., cov: 32)
• Consequence: KIT NM_001385284.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 5 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 (AMR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385284.1. 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+13234C>G		intron	N/A	NP_000213.1
	KIT	NM_001385284.1		c.67+13234C>G		intron	N/A	NP_001372213.1
	KIT	NM_001385290.1		c.67+13234C>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+13234C>G		intron	N/A	ENSP00000288135.6
	KIT	ENST00000412167.7	TSL:1	c.67+13234C>G		intron	N/A	ENSP00000390987.3
	KIT	ENST00000687109.1		c.67+13234C>G		intron	N/A	ENSP00000509371.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46805 AN: 151812 Hom.: 7852 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.310

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

GnomAD4 genome AF: 0.308 AC: 46821 AN: 151930 Hom.: 7853 Cov.: 32 AF XY: 0.305 AC XY: 22613 AN XY: 74262

African (AFR) AF: 0.193 AC: 7978 AN: 41442

American (AMR) AF: 0.403 AC: 6144 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1053 AN: 3458

East Asian (EAS) AF: 0.106 AC: 549 AN: 5176

South Asian (SAS) AF: 0.240 AC: 1154 AN: 4808

European-Finnish (FIN) AF: 0.335 AC: 3525 AN: 10526

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.374 AC: 25378 AN: 67940

Other (OTH) AF: 0.307 AC: 648 AN: 2112

Alfa AF: 0.204 Hom.: 480

Bravo AF: 0.311

Asia WGS AF: 0.159 AC: 556 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	0.010
DANN	Benign	0.39
PhyloP100		-2.3
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: rs759083; hg19: chr4-55537481;