Genetic Variant NCCRP1:p.His68Tyr (chr19-39197184-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001001414.2(NCCRP1):c.202C>T(p.His68Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000235 in 1,275,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

NCCRP1
NM_001001414.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.03

Variant links:

Genes affected

NCCRP1 (HGNC:33739): (NCCRP1, F-box associated domain containing) Predicted to contribute to ubiquitin protein ligase activity. Involved in positive regulation of cell population proliferation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NCCRP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043436497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCCRP1	NM_001001414.2 link	c.202C>T	p.His68Tyr	missense_variant	Exon 1 of 6	ENST00000339852.5	NP_001001414.1	Q6ZVX7
NCCRP1	XM_011526906.4 link	c.202C>T	p.His68Tyr	missense_variant	Exon 1 of 5		XP_011525208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCCRP1	ENST00000339852.5 link	c.202C>T	p.His68Tyr	missense_variant	Exon 1 of 6	1	NM_001001414.2	ENSP00000342137.3		Q6ZVX7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

25756

Hom.:

AF XY:

0.00

AC XY:

AN XY:

15180

show subpopulations

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:

0.0000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000235

AC:

AN:

1275164

Hom.:

Cov.:

AF XY:

0.00000320

AC XY:

AN XY:

624894

show subpopulations

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:

0.00000289

Gnomad4 OTH exome

AF:

0.00

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

Sep 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202C>T (p.H68Y) alteration is located in exon 1 (coding exon 1) of the NCCRP1 gene. This alteration results from a C to T substitution at nucleotide position 202, causing the histidine (H) at amino acid position 68 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

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.13

DANN

Benign

0.94

DEOGEN2

Benign

0.046

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.35

M_CAP

Benign

0.0089

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.76

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.57

REVEL

Benign

0.012

Sift

Benign

0.23

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.092

MutPred

0.28

Gain of phosphorylation at H68 (P = 0.026);

MVP

0.088

MPC

1.5

ClinPred

0.050

GERP RS

-6.8

Varity_R

0.045

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over