Genetic Variant NCCRP1:p.Met181Thr (chr19-39199259-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001001414.2(NCCRP1):c.542T>C(p.Met181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,613,620 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 5 hom. )

Consequence

NCCRP1
NM_001001414.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054880172).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCCRP1	NM_001001414.2 link	c.542T>C	p.Met181Thr	missense_variant	Exon 4 of 6	ENST00000339852.5	NP_001001414.1	Q6ZVX7
NCCRP1	XM_011526906.4 link	c.542T>C	p.Met181Thr	missense_variant	Exon 4 of 5		XP_011525208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCCRP1	ENST00000339852.5 link	c.542T>C	p.Met181Thr	missense_variant	Exon 4 of 6	1	NM_001001414.2	ENSP00000342137.3		Q6ZVX7

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000578

AC:

145

AN:

250992

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00626

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000351

AC:

513

AN:

1461458

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

294

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00601

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00119

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000375

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000517

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542T>C (p.M181T) alteration is located in exon 4 (coding exon 4) of the NCCRP1 gene. This alteration results from a T to C substitution at nucleotide position 542, causing the methionine (M) at amino acid position 181 to be replaced by a threonine (T). 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

0.76

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.054

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.64

M_CAP

Benign

0.012

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Benign

0.14

Sift4G

Benign

0.49

Polyphen

0.98

Vest4

0.77

MVP

0.52

MPC

0.80

ClinPred

0.038

GERP RS

5.4

Varity_R

0.18

gMVP

0.28

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