3-42635269-G-C

Variant names:

• chr3-42635269-G-C
• rs765491779
• NM_005385.4:c.1066G>C

Variant summary

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

The NM_005385.4(NKTR):​c.1066G>C​(p.Asp356His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NKTR NM_005385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

Genes affected

NKTR (HGNC:7833): (natural killer cell triggering receptor) This gene encodes a membrane-anchored protein with a hydrophobic amino terminal domain and a cyclophilin-like PPIase domain. It is present on the surface of natural killer cells and facilitates their binding to targets. Its expression is regulated by IL2 activation of the cells. [provided by RefSeq, Jul 2008]

ZBTB47-AS1 (HGNC:41174): (ZBTB47 and NKTR antisense RNA 1)

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=0.17464635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKTR	NM_005385.4	c.1066G>C	p.Asp356His	missense_variant	Exon 12 of 17	ENST00000232978.13	NP_005376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKTR	ENST00000232978.13	c.1066G>C	p.Asp356His	missense_variant	Exon 12 of 17	1	NM_005385.4	ENSP00000232978.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250718 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135504

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461570 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066G>C (p.D356H) alteration is located in exon 12 (coding exon 11) of the NKTR gene. This alteration results from a G to C substitution at nucleotide position 1066, causing the aspartic acid (D) at amino acid position 356 to be replaced by a histidine (H). 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	0.28
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.065	T;D
Polyphen		1.0	D;.
Vest4		0.29
MutPred		0.19		Loss of stability (P = 0.0461);.;
MVP		0.26
MPC		0.17
ClinPred		0.54	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs765491779; hg19: chr3-42676761;