6-150065620-T-G

Variant names:

• chr6-150065620-T-G
• rs1776334403
• NM_024518.3:c.406A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024518.3(ULBP3):​c.406A>C​(p.Ile136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ULBP3 NM_024518.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

Genes affected

ULBP3 (HGNC:14895): (UL16 binding protein 3) The protein encoded by this gene is one of several related ligands of the KLRK1/NKG2D receptor, which is found in primary NK cells. Binding of these ligands to the receptor activates several signal transduction pathways, including the JAK2, STAT5, and ERK pathways. The encoded protein is expressed solubly and on the surface of many tumor cells, making it potentially an important target for therapeutics. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07201299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ULBP3	NM_024518.3	c.406A>C	p.Ile136Leu	missense_variant	Exon 3 of 5	ENST00000367339.7	NP_078794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ULBP3	ENST00000367339.7	c.406A>C	p.Ile136Leu	missense_variant	Exon 3 of 5	5	NM_024518.3	ENSP00000356308.1
ULBP3	ENST00000438272.2	c.406A>C	p.Ile136Leu	missense_variant	Exon 3 of 4	1		ENSP00000403562.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406A>C (p.I136L) alteration is located in exon 3 (coding exon 3) of the ULBP3 gene. This alteration results from a A to C substitution at nucleotide position 406, causing the isoleucine (I) at amino acid position 136 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.28
DANN	Benign	0.94
DEOGEN2	Benign	0.0045	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.025
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.0020	B;B
Vest4		0.19
MutPred		0.37		Loss of catalytic residue at I136 (P = 0.0059);Loss of catalytic residue at I136 (P = 0.0059);
MVP		0.24
MPC		0.15
ClinPred		0.056	T
GERP RS		0.78
Varity_R		0.28
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1776334403; hg19: chr6-150386756;