11-17351974-C-A

Variant names:

• chr11-17351974-C-A
• rs988016164
• NM_001202439.3:c.5C>A

Variant summary

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

The NM_001202439.3(NCR3LG1):​c.5C>A​(p.Thr2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,349,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: NCR3LG1 NM_001202439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.166
• Publications: 1 publications found

Genes affected

NCR3LG1 (HGNC:42400): (natural killer cell cytotoxicity receptor 3 ligand 1) B7H6 belongs to the B7 family (see MIM 605402) and is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3; MIM 611550) results in natural killer (NK) cell activation and cytotoxicity (Brandt et al., 2009 [PubMed 19528259]).[supplied by OMIM, Jan 2011]

LOC105376576 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.04955855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3	c.5C>A	p.Thr2Lys	missense_variant	Exon 1 of 5	ENST00000338965.9	NP_001189368.1
NCR3LG1	XM_047426906.1	c.5C>A	p.Thr2Lys	missense_variant	Exon 1 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4	c.-727C>A		upstream_gene_variant			XP_011518376.1
LOC105376576	XR_931094.3	n.-108G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3LG1	ENST00000338965.9	c.5C>A	p.Thr2Lys	missense_variant	Exon 1 of 5	1	NM_001202439.3	ENSP00000341637.4
NCR3LG1	ENST00000530403.1	n.5C>A		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000434394.1

Frequencies

GnomAD3 genomes AF: 0.0000964 AC: 14 AN: 145282 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000182

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000704 AC: 9 AN: 127922 AF XY: 0.0000854

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.000261 AC: 314 AN: 1203736 Hom.: 0 Cov.: 31 AF XY: 0.000235 AC XY: 139 AN XY: 591816

African (AFR) AF: 0.00 AC: 0 AN: 25470

American (AMR) AF: 0.00 AC: 0 AN: 30110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18284

East Asian (EAS) AF: 0.00 AC: 0 AN: 18630

South Asian (SAS) AF: 0.00 AC: 0 AN: 77480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 0.000321 AC: 309 AN: 964116

Other (OTH) AF: 0.000109 AC: 5 AN: 46040

GnomAD4 genome AF: 0.0000963 AC: 14 AN: 145392 Hom.: 0 Cov.: 30 AF XY: 0.0000849 AC XY: 6 AN XY: 70708

African (AFR) AF: 0.0000499 AC: 2 AN: 40076

American (AMR) AF: 0.00 AC: 0 AN: 14574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 4456

South Asian (SAS) AF: 0.00 AC: 0 AN: 4294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000182 AC: 12 AN: 66036

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>A (p.T2K) alteration is located in exon 1 (coding exon 1) of the NCR3LG1 gene. This alteration results from a C to A substitution at nucleotide position 5, causing the threonine (T) at amino acid position 2 to be replaced by a lysine (K). 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	0.17
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.032	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.091
Sift	Uncertain	0.016	D
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.28		Gain of MoRF binding (P = 0.0191);
MVP		0.030
ClinPred		0.022	T
GERP RS		0.44
PromoterAI		-0.88	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.47
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: rs988016164; hg19: chr11-17373521;