19-54909315-C-G

Variant names:

• chr19-54909315-C-G
• rs2067821308
• NM_004829.7:c.426C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004829.7(NCR1):​c.426C>G​(p.Phe142Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NCR1 NM_004829.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735

Genes affected

NCR1 (HGNC:6731): (natural cytotoxicity triggering receptor 1) Predicted to be involved in cellular defense response; regulation of natural killer cell mediated cytotoxicity; and signal transduction. Predicted to act upstream of or within defense response to virus and detection of virus. Predicted to be located in cell surface. Predicted to be part of SWI/SNF complex. Predicted to be active in plasma membrane. Biomarker of acquired immunodeficiency syndrome; anogenital venereal wart; hepatitis C; and lymphoproliferative syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27174327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR1	NM_004829.7	c.426C>G	p.Phe142Leu	missense_variant	Exon 4 of 7	ENST00000291890.9	NP_004820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR1	ENST00000291890.9	c.426C>G	p.Phe142Leu	missense_variant	Exon 4 of 7	5	NM_004829.7	ENSP00000291890.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.426C>G (p.F142L) alteration is located in exon 4 (coding exon 4) of the NCR1 gene. This alteration results from a C to G substitution at nucleotide position 426, causing the phenylalanine (F) at amino acid position 142 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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.46
DEOGEN2	Benign	0.048	.;T;T;.;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.72	N;.;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;.;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.93	.;.;.;.;.;P
Vest4		0.38
MutPred		0.77		Gain of ubiquitination at K139 (P = 0.0741);.;Gain of ubiquitination at K139 (P = 0.0741);.;Gain of ubiquitination at K139 (P = 0.0741);.;
MVP		0.16
MPC		0.17
ClinPred		0.15	T
GERP RS		1.2
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2067821308; hg19: chr19-55420674;