ENST00000359085.8:c.762T>A

Variant names:

• chr19-54813180-T-A
• rs649216
• ENST00000359085.8:c.762T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000359085.8(KIR2DL4):​c.762T>A​(p.Phe254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIR2DL4 ENST00000359085.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 29 publications found

Genes affected

KIR2DL4 (HGNC:6332): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4) Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several "framework" genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response. This gene is one of the "framework" loci that is present on all haplotypes. Alternate alleles of this gene are represented on multiple alternate reference loci (ALT_REF_LOCs). Alternative splicing results in multiple transcript variants, some of which may not be annotated on the primary reference assembly. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060167253).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359085.8. 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
	KIR2DL4	NM_001080770.2	MANE Select	c.707-510T>A		intron	N/A	NP_001074239.1	Q99706-3
	KIR2DL4	NM_001080772.2		c.762T>A	p.Phe254Leu	missense	Exon 6 of 8	NP_001074241.1	A0A0B4J1S6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL4	ENST00000359085.8	TSL:1	c.762T>A	p.Phe254Leu	missense	Exon 6 of 8	ENSP00000351988.4	A0A0B4J1S6
	KIR2DL4	ENST00000345540.10	TSL:1 MANE Select	c.707-510T>A		intron	N/A	ENSP00000339634.5	Q99706-3
	KIR2DL4	ENST00000357494.8	TSL:1	c.656-510T>A		intron	N/A	ENSP00000350088.4	Q99706-4

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000216 AC: 3 AN: 1388068 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692866

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

African (AFR) AF: 0.00 AC: 0 AN: 30078

American (AMR) AF: 0.00 AC: 0 AN: 41818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24880

East Asian (EAS) AF: 0.00 AC: 0 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 82676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5102

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1056890

Other (OTH) AF: 0.00 AC: 0 AN: 57554

⚠️ 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.

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.73
DANN	Benign	0.62
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0025	N
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.89	T
PhyloP100		-0.62
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.020
Sift	Benign	0.17	T
Sift4G	Benign	0.52	T
Vest4		0.013
MVP		0.043
ClinPred		0.068	T
GERP RS		-1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs649216; hg19: chr19-55324635;