12-88507114-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000899.5(KITLG):c.628G>T(p.Asp210Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,612,446 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D210G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (214 hom.)
• Consequence: KITLG NM_000899.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 188) in uniprot entity SCF_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000899.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.009672701).
• BP6: Variant 12-88507114-C-A is Benign according to our data. Variant chr12-88507114-C-A is described in ClinVar as [Benign]. Clinvar id is 508156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1524/152272) while in subpopulation NFE AF= 0.0163 (1109/68024). AF 95% confidence interval is 0.0155. There are 12 homozygotes in gnomad4. There are 691 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KITLG	NM_000899.5	c.628G>T	p.Asp210Tyr	missense_variant	7/10	ENST00000644744.1
KITLG	NM_003994.6	c.544G>T	p.Asp182Tyr	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KITLG	ENST00000644744.1	c.628G>T	p.Asp210Tyr	missense_variant	7/10		NM_000899.5	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1523 AN: 152154 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0101 AC: 2534 AN: 250846 Hom.: 15 AF XY: 0.00991 AC XY: 1344 AN XY: 135568

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.00998

GnomAD4 exome AF: 0.0155 AC: 22687 AN: 1460174 Hom.: 214 Cov.: 29 AF XY: 0.0150 AC XY: 10920 AN XY: 726552

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00900

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00520

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0100 AC: 1524 AN: 152272 Hom.: 12 Cov.: 32 AF XY: 0.00928 AC XY: 691 AN XY: 74464

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0141 Hom.: 20

Bravo AF: 0.00893

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.0105 AC: 1272

Asia WGS AF: 0.00173 AC: 6 AN: 3474

EpiCase AF: 0.0149

EpiControl AF: 0.0152

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Asp210Tyr in exon 7 of KITLG: This variant is not expected to have clinical si gnificance because it has been identified in 1.55% (1029/66452) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs41283112). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.48	N
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
Polyphen		1.0	D;D;D
Vest4		0.58, 0.62
MPC		0.84
ClinPred		0.011	T
GERP RS		2.8
Varity_R		0.16
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs41283112; hg19: chr12-88900891;