chr2-27439869-T-A

Variant names:

• chr2-27439869-T-A
• NM_013392.4:c.1007T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_013392.4(NRBP1):​c.1007T>A​(p.Leu336His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: NRBP1 NM_013392.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013392.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRBP1	NM_013392.4	MANE Select	c.1007T>A	p.Leu336His	missense	Exon 11 of 18	NP_037524.1	Q9UHY1
	NRBP1	NM_001321358.2		c.1031T>A	p.Leu344His	missense	Exon 12 of 19	NP_001308287.1	F8W6G1
	NRBP1	NM_001321359.2		c.1031T>A	p.Leu344His	missense	Exon 12 of 19	NP_001308288.1	F8W6G1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRBP1	ENST00000379852.8	TSL:1 MANE Select	c.1007T>A	p.Leu336His	missense	Exon 11 of 18	ENSP00000369181.3	Q9UHY1
	NRBP1	ENST00000379863.7	TSL:5	c.1031T>A	p.Leu344His	missense	Exon 12 of 19	ENSP00000369192.3	F8W6G1
	NRBP1	ENST00000857545.1		c.1031T>A	p.Leu344His	missense	Exon 12 of 19	ENSP00000527604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.68		Loss of stability (P = 0.043)
MVP		0.66
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.80
Mutation Taster		=9/91	disease causing

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

hg19: chr2-27662736;