chr10-63154112-C-G

Variant names:

• chr10-63154112-C-G
• rs781140839
• NM_030759.5:c.758C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030759.5(NRBF2):​c.758C>G​(p.Ala253Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NRBF2 NM_030759.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17352128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBF2	NM_030759.5	c.758C>G	p.Ala253Gly	missense_variant	Exon 4 of 4	ENST00000277746.11	NP_110386.2
NRBF2	NM_001282405.2	c.728C>G	p.Ala243Gly	missense_variant	Exon 3 of 3		NP_001269334.1
NRBF2	XM_047425132.1	c.626C>G	p.Ala209Gly	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	c.758C>G	p.Ala253Gly	missense_variant	Exon 4 of 4	1	NM_030759.5	ENSP00000277746.6
NRBF2	ENST00000435510.6	c.728C>G	p.Ala243Gly	missense_variant	Exon 3 of 3	2		ENSP00000397502.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250502 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758C>G (p.A253G) alteration is located in exon 4 (coding exon 4) of the NRBF2 gene. This alteration results from a C to G substitution at nucleotide position 758, causing the alanine (A) at amino acid position 253 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	.;T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	.;L
PhyloP100		3.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.061
Sift	Benign	0.21	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.017	.;B
Vest4		0.087
MutPred		0.65		.;Gain of relative solvent accessibility (P = 0.0507);
MVP		0.81
MPC		0.16
ClinPred		0.30	T
GERP RS		5.8
Varity_R		0.076
gMVP		0.066
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs781140839; hg19: chr10-64913872;