Genetic Variant NM_000899.5:c.130-12_130-11dupTT (chr12-88532513-C-CAA) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_000899.5(KITLG):c.130-12_130-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,305,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00086 ( 0 hom. )

Consequence

KITLG
NM_000899.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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 Submitted by: Labcorp Genetics (formerly Invitae)
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: Orphanet, G2P
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Waardenburg syndrome, IIa 2F
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

KITLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 12-88532513-C-CAA is Benign according to our data. Variant chr12-88532513-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 3628555.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000425 (6/141150) while in subpopulation AFR AF = 0.000157 (6/38306). AF 95% confidence interval is 0.0000681. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000899.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	NM_000899.5	MANE Select	c.130-12_130-11dupTT		intron	N/A	NP_000890.1	P21583-1
	KITLG	NM_003994.6		c.130-12_130-11dupTT		intron	N/A	NP_003985.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KITLG	ENST00000644744.1	MANE Select	c.130-11_130-10insTT	intron	N/A	ENSP00000495951.1	P21583-1
KITLG	ENST00000347404.10	TSL:1	c.130-11_130-10insTT	intron	N/A	ENSP00000054216.5	P21583-2
KITLG	ENST00000378535.4	TSL:1	n.73-11_73-10insTT	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000425

AC:

AN:

141098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000741

AC:

AN:

118740

AF XY:

0.000852

show subpopulations

Gnomad AFR exome

AF:

0.000477

Gnomad AMR exome

AF:

0.00129

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.000142

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.000574

Gnomad OTH exome

AF:

0.000375

GnomAD4 exome

AF:

0.000861

AC:

1002

AN:

1163898

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

493

AN XY:

577512

show subpopulations

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

African (AFR)

AF:

0.00106

AC:

AN:

25582

American (AMR)

AF:

0.000592

AC:

AN:

32070

Ashkenazi Jewish (ASJ)

AF:

0.000360

AC:

AN:

19446

East Asian (EAS)

AF:

0.000137

AC:

AN:

29134

South Asian (SAS)

AF:

0.00100

AC:

AN:

64902

European-Finnish (FIN)

AF:

0.000511

AC:

AN:

41058

Middle Eastern (MID)

AF:

0.000450

AC:

AN:

4448

European-Non Finnish (NFE)

AF:

0.000911

AC:

820

AN:

900096

Other (OTH)

AF:

0.000785

AC:

AN:

47162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

119

238

358

477

596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.0000425

AC:

AN:

141150

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

68410

show subpopulations

African (AFR)

AF:

0.000157

AC:

AN:

38306

American (AMR)

AF:

0.00

AC:

AN:

14080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3318

East Asian (EAS)

AF:

0.00

AC:

AN:

4840

South Asian (SAS)

AF:

0.00

AC:

AN:

4492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64484

Other (OTH)

AF:

0.00

AC:

AN:

1950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.000554

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over