12-88505215-C-G

Variant names:

• chr12-88505215-C-G
• NM_000899.5:c.803G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000899.5(KITLG):​c.803G>C​(p.Arg268Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KITLG NM_000899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

Genes affected

KITLG (HGNC:6343): (KIT ligand) This gene encodes the ligand of the tyrosine-kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development, and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KITLG	NM_000899.5	c.803G>C	p.Arg268Thr	missense_variant	Exon 9 of 10	ENST00000644744.1	NP_000890.1
KITLG	NM_003994.6	c.719G>C	p.Arg240Thr	missense_variant	Exon 8 of 9		NP_003985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KITLG	ENST00000644744.1	c.803G>C	p.Arg268Thr	missense_variant	Exon 9 of 10		NM_000899.5	ENSP00000495951.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458884 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803G>C (p.R268T) alteration is located in exon 9 (coding exon 9) of the KITLG gene. This alteration results from a G to C substitution at nucleotide position 803, causing the arginine (R) at amino acid position 268 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M;.;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	.;N;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.020	.;D;D;.
Sift4G	Benign	0.066	.;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.47, 0.47, 0.40
MutPred		0.51		Gain of phosphorylation at R268 (P = 0.0559);.;Gain of phosphorylation at R268 (P = 0.0559);.;
MVP		0.68
MPC		0.93
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-88898992;