2-27441749-G-C

Variant names:

• chr2-27441749-G-C
• rs1664578175
• NM_013392.4:c.1545G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013392.4(NRBP1):​c.1545G>C​(p.Leu515Phe) 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: NRBP1 NM_013392.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.778

Genes affected

NRBP1 (HGNC:7993): (nuclear receptor binding protein 1) Predicted to enable protein homodimerization activity. Involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Located in endomembrane system. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.05471906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBP1	NM_013392.4	c.1545G>C	p.Leu515Phe	missense_variant	Exon 18 of 18	ENST00000379852.8	NP_037524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRBP1	ENST00000379852.8	c.1545G>C	p.Leu515Phe	missense_variant	Exon 18 of 18	1	NM_013392.4	ENSP00000369181.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1545G>C (p.L515F) alteration is located in exon 18 (coding exon 17) of the NRBP1 gene. This alteration results from a G to C substitution at nucleotide position 1545, causing the leucine (L) at amino acid position 515 to be replaced by a phenylalanine (F). 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	0.044
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.080
MutPred		0.26		.;.;Gain of methylation at K525 (P = 0.086);
MVP		0.15
MPC		0.66
ClinPred		0.24	T
GERP RS		0.93
Varity_R		0.12
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1664578175; hg19: chr2-27664616;