4-54733155-AC-CA

Variant names:

• chr4-54733155-AC-CA
• NM_000222.3:c.2447_2448delACinsCA
• KIT p.Asp816Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000222.3(KIT):c.2447_2448delACinsCA (p.Asp816Ala) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.22). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D816H: Pathogenic (ClinVar VariationId 13863, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D816= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 286360); p.D816G: Uncertain_significance (ClinVar VariationId 1968176, 1 star); p.D816Y: Uncertain_significance (ClinVar VariationId 13860, 1 star) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. The variant position is a cancer hotspot (cancerhotspots.org): 22 samples carry this exact amino acid change out of 88 samples with a variant at this residue.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.22
• 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• piebaldism

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

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

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 0 benign (OR vs. background: 65.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D816H: Pathogenic (ClinVar VariationId 13863, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.D816= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 286360); p.D816G: Uncertain_significance (ClinVar VariationId 1968176, 1 star); p.D816Y: Uncertain_significance (ClinVar VariationId 13860, 1 star)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000222.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIT NM_000222.3	MANE Select	c.2447_2448delACinsCA p.Asp816Ala	missense	N/A	Prot: NP_000213.1 UniProt:
	KIT NM_001385284.1		c.2450_2451delACinsCA p.Asp817Ala	missense	N/A	Prot: NP_001372213.1 UniProt:
	KIT NM_001385290.1		c.2447_2448delACinsCA p.Asp816Ala	missense	N/A	Prot: NP_001372219.1 UniProt:

KIT NM_000222.3

MANE Select

HGVSc / HGVSpc.2447_2448delACinsCAp.Asp816Ala

Exon rankN/A

missense

Prot: NP_000213.1UniProt: P10721-1

KIT NM_001385284.1

HGVSc / HGVSpc.2450_2451delACinsCAp.Asp817Ala

Exon rankN/A

missense

Prot: NP_001372213.1UniProt: A0A8I5KS03

KIT NM_001385290.1

HGVSc / HGVSpc.2447_2448delACinsCAp.Asp816Ala

Exon rankN/A

missense

Prot: NP_001372219.1UniProt: A0A8I5QKP7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIT ENST00000288135.6	TSL:1MANE Select	c.2447_2448delACinsCA p.Asp816Ala	missense	N/A	Prot: ENSP00000288135.6 UniProt:
	KIT ENST00000412167.7	TSL:1	c.2435_2436delACinsCA p.Asp812Ala	missense	N/A	Prot: ENSP00000390987.3 UniProt:
	KIT ENST00000687109.1		c.2450_2451delACinsCA p.Asp817Ala	missense	N/A	Prot: ENSP00000509371.1 UniProt:

KIT ENST00000288135.6

TSL:1MANE Select

HGVSc / HGVSpc.2447_2448delACinsCAp.Asp816Ala

Exon rankN/A

missense

Prot: ENSP00000288135.6UniProt: P10721-1

KIT ENST00000412167.7

TSL:1

HGVSc / HGVSpc.2435_2436delACinsCAp.Asp812Ala

Exon rankN/A

missense

Prot: ENSP00000390987.3UniProt: A0A8J8Z860

KIT ENST00000687109.1

HGVSc / HGVSpc.2450_2451delACinsCAp.Asp817Ala

Exon rankN/A

missense

Prot: ENSP00000509371.1UniProt: A0A8I5KS03

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr4-55599321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar