Genetic Variant NCR3LG1:p.Cys48Tyr (chr11-17356723-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001202439.3(NCR3LG1):c.143G>A(p.Cys48Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000361 in 1,384,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

NCR3LG1
NM_001202439.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

Publications

0 publications found

Variant links:

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]

NCR3LG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3 link	c.143G>A	p.Cys48Tyr	missense_variant	Exon 2 of 5	ENST00000338965.9	NP_001189368.1	Q68D85
NCR3LG1	XM_047426906.1 link	c.143G>A	p.Cys48Tyr	missense_variant	Exon 2 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 2 of 5		XP_011518376.1
NCR3LG1	XM_011520075.4 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 2 of 5		XP_011518377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3LG1	ENST00000338965.9 link	c.143G>A	p.Cys48Tyr	missense_variant	Exon 2 of 5	1	NM_001202439.3	ENSP00000341637.4		Q68D85
NCR3LG1	ENST00000530403.1 link	n.143G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000434394.1		Q68D85

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1384104

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

682986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1078946

Other (OTH)

AF:

0.00

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.143G>A (p.C48Y) alteration is located in exon 2 (coding exon 2) of the NCR3LG1 gene. This alteration results from a G to A substitution at nucleotide position 143, causing the cysteine (C) at amino acid position 48 to be replaced by a tyrosine (Y). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.62

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

3.7

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.78

Loss of catalytic residue at I46 (P = 0.1314);

MVP

0.26

ClinPred

0.89

GERP RS

4.3

Varity_R

0.88

gMVP

0.91

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

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11-17356723-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over