4-54709415-T-C

Variant names:

• chr4-54709415-T-C
• rs1553889072
• NM_000222.3:c.1116-9T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000222.3(KIT):​c.1116-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,412,162 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: KIT NM_000222.3 intron
• Scores: Splicing: ADA: 0.00003713
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.312
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-54709415-T-C is Benign according to our data. Variant chr4-54709415-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 458853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 32 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.1116-9T>C		intron	N/A	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.1119-9T>C		intron	N/A	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.1119-9T>C		intron	N/A	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.1116-9T>C		intron	N/A	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.1119-9T>C		intron	N/A	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.1119-9T>C		intron	N/A	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000227 AC: 32 AN: 1412162 Hom.: 0 Cov.: 25 AF XY: 0.0000212 AC XY: 15 AN XY: 705990

African (AFR) AF: 0.00 AC: 0 AN: 32398

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 85280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000272 AC: 29 AN: 1066748

Other (OTH) AF: 0.0000511 AC: 3 AN: 58746

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Gastrointestinal stromal tumor (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.38
PhyloP100		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0060
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: rs1553889072; hg19: chr4-55575581;