NM_000222.3:c.2447A>T

Variant names:

• chr4-54733155-A-T
• rs121913507
• NM_000222.3:c.2447A>T
• KIT p.Asp816Val

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_ModeratePP5

The NM_000222.3(KIT):c.2447A>T (p.Asp816Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000072, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.22). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV005042656: Experimental studies show that this variant leads to an ligand-independent activation and it gains extra activity via different signaling pathways from that of wild-type KIT Ke et al. 2016.". 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) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4 O:2
• Conservation: PhyloP100: 9.22
• Publications: 1895 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: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005042656: Experimental studies show that this variant leads to an ligand-independent activation and it gains extra activity via different signaling pathways from that of wild-type KIT Ke et al. 2016.
	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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000072 — very rare for AD/XL gene (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)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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.2447A>T p.Asp816Val	missense	Exon 17 of 21	Prot: NP_000213.1 UniProt:
	KIT NM_001385284.1		c.2450A>T p.Asp817Val	missense	Exon 17 of 21	Prot: NP_001372213.1 UniProt:
	KIT NM_001385290.1		c.2447A>T p.Asp816Val	missense	Exon 17 of 21	Prot: NP_001372219.1 UniProt:

KIT NM_000222.3

MANE Select

HGVSc / HGVSpc.2447A>Tp.Asp816Val

Exon rankExon 17 of 21

missense

Prot: NP_000213.1UniProt: P10721-1

KIT NM_001385284.1

HGVSc / HGVSpc.2450A>Tp.Asp817Val

Exon rankExon 17 of 21

missense

Prot: NP_001372213.1UniProt: A0A8I5KS03

KIT NM_001385290.1

HGVSc / HGVSpc.2447A>Tp.Asp816Val

Exon rankExon 17 of 21

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.2447A>T p.Asp816Val	missense	Exon 17 of 21	Prot: ENSP00000288135.6 UniProt:
	KIT ENST00000412167.7	TSL:1	c.2435A>T p.Asp812Val	missense	Exon 17 of 21	Prot: ENSP00000390987.3 UniProt:
	KIT ENST00000687109.1		c.2450A>T p.Asp817Val	missense	Exon 17 of 21	Prot: ENSP00000509371.1 UniProt:

KIT ENST00000288135.6

TSL:1MANE Select

HGVSc / HGVSpc.2447A>Tp.Asp816Val

Exon rankExon 17 of 21

missense

Prot: ENSP00000288135.6UniProt: P10721-1

KIT ENST00000412167.7

TSL:1

HGVSc / HGVSpc.2435A>Tp.Asp812Val

Exon rankExon 17 of 21

missense

Prot: ENSP00000390987.3UniProt: A0A8J8Z860

KIT ENST00000687109.1

HGVSc / HGVSpc.2450A>Tp.Asp817Val

Exon rankExon 17 of 21

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:251128	Cov:
GnomAD4 exome Warning	AF: 0.00000205	AC:3	Hom:0	AN:1460592	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000468	AC:1	Hom:0	AN:21346	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41952	0.0000150	1	66786

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Cutaneous mastocytosis (4)
-	2	-	Gastrointestinal stromal tumor (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	MAST CELL LEUKEMIA, SOMATIC (1)
1	-	-	MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC DISORDER, SOMATIC (1)
1	-	-	MASTOCYTOSIS, SYSTEMIC, SOMATIC (1)
1	-	-	not provided (1)
-	-	-	Dysgerminoma (1)
-	-	-	Germinoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.30	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	0.095	N
PhyloP100	Pathogenic	9.2
popEVE	Uncertain	-5.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.95
VESM-3B	Benign	-14

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs121913507;

hg19: chr4-55599321;

COSMIC: COSV55386424;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar