Genetic Variant KITLG:c.130-11delT (chr12-88532513-CA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000899.5(KITLG):c.130-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,162,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.034 ( 0 hom. )

Consequence

KITLG
NM_000899.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.318

Publications

3 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: Benign. The variant received -8 ACMG points.

BP6

Variant 12-88532513-CA-C is Benign according to our data. Variant chr12-88532513-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1272999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KITLG	NM_000899.5 link	c.130-11delT		intron_variant	Intron 2 of 9	ENST00000644744.1	NP_000890.1	P21583-1A0A024RBC0
KITLG	NM_003994.6 link	c.130-11delT		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.130-11delT		intron_variant	Intron 2 of 9		NM_000899.5	ENSP00000495951.1		P21583-1

Frequencies

GnomAD3 genomes

AF:

0.000397

AC:

AN:

140946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000711

Gnomad ASJ

AF:

0.000603

Gnomad EAS

AF:

0.000206

Gnomad SAS

AF:

0.000222

Gnomad FIN

AF:

0.00129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000341

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0513

AC:

6095

AN:

118740

AF XY:

0.0500

show subpopulations

Gnomad AFR exome

AF:

0.0347

Gnomad AMR exome

AF:

0.0901

Gnomad ASJ exome

AF:

0.0734

Gnomad EAS exome

AF:

0.0726

Gnomad FIN exome

AF:

0.0535

Gnomad NFE exome

AF:

0.0380

Gnomad OTH exome

AF:

0.0687

GnomAD4 exome

AF:

0.0335

AC:

34257

AN:

1021590

Hom.:

Cov.:

AF XY:

0.0334

AC XY:

16757

AN XY:

502458

show subpopulations

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

African (AFR)

AF:

0.0369

AC:

818

AN:

22190

American (AMR)

AF:

0.0589

AC:

1560

AN:

26490

Ashkenazi Jewish (ASJ)

AF:

0.0430

AC:

672

AN:

15622

East Asian (EAS)

AF:

0.0404

AC:

898

AN:

22208

South Asian (SAS)

AF:

0.0448

AC:

2394

AN:

53452

European-Finnish (FIN)

AF:

0.0412

AC:

1396

AN:

33860

Middle Eastern (MID)

AF:

0.0263

AC:

104

AN:

3958

European-Non Finnish (NFE)

AF:

0.0311

AC:

24955

AN:

803350

Other (OTH)

AF:

0.0361

AC:

1460

AN:

40460

⚠️ 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: 0.250

Heterozygous variant carriers

4940

9881

14821

19762

24702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

952

1904

2856

3808

4760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000397

AC:

AN:

140992

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

68318

show subpopulations

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

African (AFR)

AF:

0.000235

AC:

AN:

38280

American (AMR)

AF:

0.000711

AC:

AN:

14070

Ashkenazi Jewish (ASJ)

AF:

0.000603

AC:

AN:

3318

East Asian (EAS)

AF:

0.000207

AC:

AN:

4836

South Asian (SAS)

AF:

0.000223

AC:

AN:

4490

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

8496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000342

AC:

AN:

64420

Other (OTH)

AF:

0.00

AC:

AN:

1950

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0493

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.32

Mutation Taster

=99/1

polymorphism

(source)

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

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12-88532513-CAAAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over