19-54906715-T-G

Variant names:

• chr19-54906715-T-G
• rs1569536504
• NM_004829.7:c.263T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004829.7(NCR1):​c.263T>G​(p.Met88Arg) 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 1,461,886 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: 6.8e-7 (0 hom.)
• Consequence: NCR1 NM_004829.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR1	NM_004829.7	c.263T>G	p.Met88Arg	missense_variant	Exon 3 of 7	ENST00000291890.9	NP_004820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR1	ENST00000291890.9	c.263T>G	p.Met88Arg	missense_variant	Exon 3 of 7	5	NM_004829.7	ENSP00000291890.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263T>G (p.M88R) alteration is located in exon 3 (coding exon 3) of the NCR1 gene. This alteration results from a T to G substitution at nucleotide position 263, causing the methionine (M) at amino acid position 88 to be replaced by an arginine (R). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.18	.;T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.0051	T
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.78	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.6	D;.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D
Vest4		0.78
MutPred		0.75		Gain of MoRF binding (P = 0.0342);.;Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);
MVP		0.51
MPC		0.70
ClinPred		0.91	D
GERP RS		3.7
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1569536504; hg19: chr19-55418073;