19-54727771-C-T

Variant names:

• chr19-54727771-C-T
• rs546562878
• NM_153443.5:c.516C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_153443.5(KIR3DL3):​c.516C>T​(p.His172His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,464 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., cov: 30)
  • Exomes 𝑓: 0.012 (137 hom.)
• Consequence: KIR3DL3 NM_153443.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 2 publications found

Genes affected

KIR3DL3 (HGNC:16312): (killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3) 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. [provided by RefSeq, Jul 2008]

ENSG00000215765 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 19-54727771-C-T is Benign according to our data. Variant chr19-54727771-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2650458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR3DL3	NM_153443.5	c.516C>T	p.His172His	synonymous_variant	Exon 4 of 8	ENST00000291860.2	NP_703144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR3DL3	ENST00000291860.2	c.516C>T	p.His172His	synonymous_variant	Exon 4 of 8	1	NM_153443.5	ENSP00000291860.1
ENSG00000215765	ENST00000400864.3	n.35+3241C>T		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1372 AN: 151546 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00961

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00772

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182526 AF XY: 0.0000203

Gnomad AFR exome AF: 0.0000709

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0117 AC: 17066 AN: 1461800 Hom.: 137 Cov.: 35 AF XY: 0.0114 AC XY: 8294 AN XY: 727200

African (AFR) AF: 0.00224 AC: 75 AN: 33480

American (AMR) AF: 0.00436 AC: 195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0115 AC: 989 AN: 86252

European-Finnish (FIN) AF: 0.00930 AC: 497 AN: 53420

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14565 AN: 1111932

Other (OTH) AF: 0.0101 AC: 610 AN: 60392

GnomAD4 genome AF: 0.00905 AC: 1372 AN: 151664 Hom.: 7 Cov.: 30 AF XY: 0.00901 AC XY: 667 AN XY: 74064

African (AFR) AF: 0.00287 AC: 119 AN: 41448

American (AMR) AF: 0.00637 AC: 97 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4998

South Asian (SAS) AF: 0.00962 AC: 46 AN: 4784

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 866 AN: 67900

Other (OTH) AF: 0.00764 AC: 16 AN: 2094

Alfa AF: 0.00860 Hom.: 0

Bravo AF: 0.00870

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIR3DL3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.2
DANN	Benign	0.66
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs546562878; hg19: chr19-55239237; COSMIC: COSV52547469;