Genetic Variant KITLG:c.130-14_130-11dupTTTT (chr12-88532513-C-CAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000899.5(KITLG):c.130-14_130-11dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000857 in 1,167,032 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

KITLG
NM_000899.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.318

Publications

0 publications found

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 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

KITLG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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.130-14_130-11dupTTTT		intron_variant	Intron 2 of 9	ENST00000644744.1	NP_000890.1	P21583-1A0A024RBC0
KITLG	NM_003994.6 link	c.130-14_130-11dupTTTT		intron_variant	Intron 2 of 8		NP_003985.2	P21583-2A0A024RBF5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KITLG	ENST00000644744.1 link	c.130-11_130-10insTTTT		intron_variant	Intron 2 of 9		NM_000899.5	ENSP00000495951.1		P21583-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.57e-7

AC:

AN:

1167032

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

579070

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25652

American (AMR)

AF:

0.00

AC:

AN:

32136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19480

East Asian (EAS)

AF:

0.00

AC:

AN:

29170

South Asian (SAS)

AF:

0.0000153

AC:

AN:

65172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

902546

Other (OTH)

AF:

0.00

AC:

AN:

47280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-88532513-CAAAA-CAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over