Genetic Variant NM_000899.5:c.753A>G (chr12-88506340-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000899.5(KITLG):c.753A>G(p.Ile251Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,194 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: 6.9e-7 ( 0 hom. )

Consequence

KITLG
NM_000899.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Variant links:

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]

KITLG links:

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ACMG classification

Classification made for transcript

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 link	c.753A>G	p.Ile251Met	missense_variant	Exon 8 of 10	ENST00000644744.1	NP_000890.1	P21583-1A0A024RBC0
KITLG	NM_003994.6 link	c.669A>G	p.Ile223Met	missense_variant	Exon 7 of 9		NP_003985.2	P21583-2A0A024RBF5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KITLG	ENST00000644744.1 link	c.753A>G	p.Ile251Met	missense_variant	Exon 8 of 10		NM_000899.5	ENSP00000495951.1		P21583-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.753A>G (p.I251M) alteration is located in exon 8 (coding exon 8) of the KITLG gene. This alteration results from a A to G substitution at nucleotide position 753, causing the isoleucine (I) at amino acid position 251 to be replaced by a methionine (M). 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

Benign

0.11

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;T;T;T

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

2.0

M;.;M;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.81

.;N;N;.

REVEL

Benign

0.23

Sift

Benign

0.035

.;D;D;.

Sift4G

Uncertain

0.015

.;D;D;D

Polyphen

0.90

P;P;P;.

Vest4

0.29, 0.27, 0.28

MutPred

0.68

Gain of disorder (P = 0.0527);.;Gain of disorder (P = 0.0527);.;

MVP

0.52

MPC

0.67

ClinPred

0.73

GERP RS

5.2

Varity_R

0.21

gMVP

0.097

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over