12-88518750-G-C

Variant names:

• chr12-88518750-G-C
• rs864309655
• NM_000899.5:c.310C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000644744.1(KITLG):​c.310C>G​(p.Leu104Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KITLG ENST00000644744.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.02
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 69

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hyperpigmentation with or without hypopigmentation, familial progressive

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial progressive hyper- and hypopigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial progressive hyperpigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Waardenburg syndrome, IIa 2F

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644744.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	NM_000899.5	MANE Select	c.310C>G	p.Leu104Val	missense	Exon 4 of 10	NP_000890.1
	KITLG	NM_003994.6		c.310C>G	p.Leu104Val	missense	Exon 4 of 9	NP_003985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	ENST00000644744.1	MANE Select	c.310C>G	p.Leu104Val	missense	Exon 4 of 10	ENSP00000495951.1
	KITLG	ENST00000347404.10	TSL:1	c.310C>G	p.Leu104Val	missense	Exon 4 of 9	ENSP00000054216.5
	KITLG	ENST00000378535.4	TSL:1	n.253C>G		non_coding_transcript_exon	Exon 3 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.77		Gain of ubiquitination at K103 (P = 0.0822)
MVP		0.60
MPC		0.77
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.67
gMVP		0.68
Mutation Taster		=20/80	disease causing

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: rs864309655; hg19: chr12-88912527;