Genetic Variant NRBF2:p.Ala53Thr (chr10-63153511-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_030759.5(NRBF2):c.157G>A(p.Ala53Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,600,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NRBF2
NM_030759.5 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.77

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBF2	NM_030759.5 link	c.157G>A	p.Ala53Thr	missense_variant, splice_region_variant	Exon 4 of 4	ENST00000277746.11	NP_110386.2	Q96F24-1
NRBF2	NM_001282405.2 link	c.127G>A	p.Ala43Thr	missense_variant, splice_region_variant	Exon 3 of 3		NP_001269334.1	Q96F24-3
NRBF2	XM_047425132.1 link	c.25G>A	p.Ala9Thr	missense_variant, splice_region_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.157G>A	p.Ala53Thr	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_030759.5	ENSP00000277746.6		Q96F24-1
NRBF2	ENST00000435510.6 link	c.127G>A	p.Ala43Thr	missense_variant, splice_region_variant	Exon 3 of 3	2		ENSP00000397502.2		Q96F24-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000246

AC:

AN:

243912

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132446

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:

0.0000542

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1448414

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

720336

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:

0.0000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

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

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157G>A (p.A53T) alteration is located in exon 4 (coding exon 4) of the NRBF2 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the alanine (A) at amino acid position 53 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

0.91

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

.;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.0

D;N

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

.;D

Vest4

0.88

MutPred

0.62

.;Loss of helix (P = 0.0104);

MVP

0.85

MPC

0.26

ClinPred

0.38

GERP RS

5.4

Varity_R

0.57

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.030

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