rs3822214

Variant names:

• chr4-54727298-A-C
• rs3822214
• NM_000222.3:c.1621A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-54727298-A-C
• chr4-54727298-A-T
• chr4-54727298-A-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000222.3(KIT):​c.1621A>C​(p.Met541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 1,613,890 control chromosomes in the GnomAD database, including 7,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M541T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.077 (506 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7400 hom.)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12 O:1
• Conservation: PhyloP100: 1.03
• Publications: 245 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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 22 uncertain in NM_000222.3
• PP2: Missense variant in the KIT gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.5806 (below the threshold of 3.09). Trascript score misZ: 4.1549 (above the threshold of 3.09). GenCC associations: The gene is linked to cutaneous mastocytosis, gastrointestinal stromal tumor, mastocytosis, piebaldism.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028303266).
• BP6: Variant 4-54727298-A-C is Benign according to our data. Variant chr4-54727298-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0971 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.1621A>C	p.Met541Leu	missense	Exon 10 of 21	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.1624A>C	p.Met542Leu	missense	Exon 10 of 21	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.1624A>C	p.Met542Leu	missense	Exon 10 of 21	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.1621A>C	p.Met541Leu	missense	Exon 10 of 21	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.1612A>C	p.Met538Leu	missense	Exon 10 of 21	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.1624A>C	p.Met542Leu	missense	Exon 10 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 11752 AN: 152146 Hom.: 505 Cov.: 32

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0487

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0771 AC: 19379 AN: 251206 AF XY: 0.0799

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.0486

Gnomad ASJ exome AF: 0.0974

Gnomad EAS exome AF: 0.0469

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0979

Gnomad OTH exome AF: 0.0879

GnomAD4 exome AF: 0.0972 AC: 142075 AN: 1461626 Hom.: 7400 Cov.: 33 AF XY: 0.0967 AC XY: 70320 AN XY: 727146

African (AFR) AF: 0.0609 AC: 2040 AN: 33474

American (AMR) AF: 0.0505 AC: 2259 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 2556 AN: 26134

East Asian (EAS) AF: 0.0487 AC: 1933 AN: 39694

South Asian (SAS) AF: 0.0773 AC: 6669 AN: 86248

European-Finnish (FIN) AF: 0.0461 AC: 2462 AN: 53420

Middle Eastern (MID) AF: 0.0791 AC: 456 AN: 5766

European-Non Finnish (NFE) AF: 0.106 AC: 117931 AN: 1111776

Other (OTH) AF: 0.0955 AC: 5769 AN: 60392

GnomAD4 genome AF: 0.0772 AC: 11750 AN: 152264 Hom.: 506 Cov.: 32 AF XY: 0.0726 AC XY: 5405 AN XY: 74460

African (AFR) AF: 0.0593 AC: 2463 AN: 41542

American (AMR) AF: 0.0662 AC: 1012 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3472

East Asian (EAS) AF: 0.0488 AC: 253 AN: 5184

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4826

European-Finnish (FIN) AF: 0.0360 AC: 382 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6740 AN: 68014

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0909 Hom.: 2686

Bravo AF: 0.0794

TwinsUK AF: 0.109 AC: 404

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.0635 AC: 280

ESP6500EA AF: 0.112 AC: 962

ExAC AF: 0.0789 AC: 9575

Asia WGS AF: 0.0750 AC: 261 AN: 3478

EpiCase AF: 0.0994

EpiControl AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Gastrointestinal stromal tumor (3)
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
1	-	-	Lip and oral cavity carcinoma (1)
-	-	1	Mastocytosis (1)
-	-	1	Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.49
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.38	N
PhyloP100		1.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.42
Sift	Benign	0.80	T
Sift4G	Benign	0.81	T
Polyphen		0.012	B
Vest4		0.45
MutPred		0.14		Gain of catalytic residue at M541 (P = 0.0666)
MPC		0.41
ClinPred		0.000031	T
GERP RS		1.8
Varity_R		0.059
gMVP		0.69
Mutation Taster		=39/40	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: rs3822214; hg19: chr4-55593464; COSMIC: COSV55388500; COSMIC: COSV55388500;