Genetic Variant NRBF2:p.Glu188Asp (chr10-63153918-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030759.5(NRBF2):c.564G>C(p.Glu188Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000993 in 1,611,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

NRBF2
NM_030759.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55

Variant links:

Genes affected

NRBF2 (HGNC:19692): (nuclear receptor binding factor 2) Involved in autophagy. Located in cytoplasm. Colocalizes with phosphatidylinositol 3-kinase complex, class III. [provided by Alliance of Genome Resources, Apr 2022]

NRBF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08065027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBF2	NM_030759.5 link	c.564G>C	p.Glu188Asp	missense_variant	Exon 4 of 4	ENST00000277746.11	NP_110386.2	Q96F24-1
NRBF2	NM_001282405.2 link	c.534G>C	p.Glu178Asp	missense_variant	Exon 3 of 3		NP_001269334.1	Q96F24-3
NRBF2	XM_047425132.1 link	c.432G>C	p.Glu144Asp	missense_variant	Exon 3 of 3		XP_047281088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRBF2	ENST00000277746.11 link	c.564G>C	p.Glu188Asp	missense_variant	Exon 4 of 4	1	NM_030759.5	ENSP00000277746.6		Q96F24-1
NRBF2	ENST00000435510.6 link	c.534G>C	p.Glu178Asp	missense_variant	Exon 3 of 3	2		ENSP00000397502.2		Q96F24-3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

249520

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135386

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:

0.000786

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000932

AC:

136

AN:

1459634

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726120

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:

0.000992

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.000158

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000559

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.564G>C (p.E188D) alteration is located in exon 4 (coding exon 4) of the NRBF2 gene. This alteration results from a G to C substitution at nucleotide position 564, causing the glutamic acid (E) at amino acid position 188 to be replaced by an aspartic acid (D). 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

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

.;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

.;M

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.10

Sift

Benign

0.071

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.46

.;P

Vest4

0.20

MutPred

0.52

.;Loss of helix (P = 0.0104);

MVP

0.75

MPC

0.20

ClinPred

0.14

GERP RS

4.8

Varity_R

0.19

gMVP

0.19

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