chr3-52563415-C-A

Variant names:

• chr3-52563415-C-A
• rs1336911500
• NM_001405607.1:c.3999G>T

Variant summary

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

The NM_001405607.1(PBRM1):​c.3999G>T​(p.Glu1333Asp) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1333K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PBRM1 NM_001405607.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.573
• Publications: 0 publications found

Genes affected

PBRM1 (HGNC:30064): (polybromo 1) This locus encodes a subunit of ATP-dependent chromatin-remodeling complexes. The encoded protein has been identified as in integral component of complexes necessary for ligand-dependent transcriptional activation by nuclear hormone receptors. Mutations at this locus have been associated with primary clear cell renal cell carcinoma. [provided by RefSeq, Feb 2012]

UQCC5 (HGNC:37257): (ubiquinol-cytochrome c reductase complex assembly factor 5) Predicted to be integral component of membrane. [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=0.09379983).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405607.1. 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
	PBRM1	NM_001405607.1	MANE Select	c.3999G>T	p.Glu1333Asp	missense	Exon 26 of 32	NP_001392536.1	A0A9L9PXL4
	PBRM1	NM_001405601.1		c.3999G>T	p.Glu1333Asp	missense	Exon 26 of 32	NP_001392530.1	A0A9L9PXL4
	PBRM1	NM_001405598.1		c.3981G>T	p.Glu1327Asp	missense	Exon 25 of 31	NP_001392527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBRM1	ENST00000707071.1	MANE Select	c.3999G>T	p.Glu1333Asp	missense	Exon 26 of 32	ENSP00000516722.1	A0A9L9PXL4
	PBRM1	ENST00000296302.11	TSL:1	c.3954G>T	p.Glu1318Asp	missense	Exon 24 of 30	ENSP00000296302.7	Q86U86-1
	PBRM1	ENST00000409114.7	TSL:1	c.3999G>T	p.Glu1333Asp	missense	Exon 25 of 30	ENSP00000386643.3	Q86U86-8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.57
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.11
Sift	Benign	0.42	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.18		Loss of sheet (P = 0.0315)
MVP		0.38
MPC		0.81
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.085
gMVP		0.20
Mutation Taster		=93/7	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: rs1336911500; hg19: chr3-52597431;