Genetic Variant PBRM1:p.Asp1652His (chr3-52548224-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001405607.1(PBRM1):c.4954G>C(p.Asp1652His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,480 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1652N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PBRM1
NM_001405607.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

Publications

0 publications found

Variant links:

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]

PBRM1 links:

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]

UQCC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PBRM1	NM_001405607.1	MANE Select	c.4954G>C	p.Asp1652His	missense	Exon 32 of 32	NP_001392536.1
PBRM1	NM_001405601.1		c.4954G>C	p.Asp1652His	missense	Exon 32 of 32	NP_001392530.1
PBRM1	NM_001405598.1		c.4936G>C	p.Asp1646His	missense	Exon 31 of 31	NP_001392527.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PBRM1	ENST00000707071.1	MANE Select	c.4954G>C	p.Asp1652His	missense	Exon 32 of 32	ENSP00000516722.1
PBRM1	ENST00000296302.11	TSL:1	c.4909G>C	p.Asp1637His	missense	Exon 30 of 30	ENSP00000296302.7
PBRM1	ENST00000409114.7	TSL:1	c.4798G>C	p.Asp1600His	missense	Exon 30 of 30	ENSP00000386643.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705882

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30700

American (AMR)

AF:

0.00

AC:

AN:

33230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25106

East Asian (EAS)

AF:

0.00

AC:

AN:

37592

South Asian (SAS)

AF:

0.00

AC:

AN:

78264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098096

Other (OTH)

AF:

0.00

AC:

AN:

58738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

PhyloP100

7.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.26

Sift

Uncertain

0.010

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.70

MutPred

0.21

Loss of ubiquitination at K1642 (P = 0.0261)

MVP

0.50

MPC

1.6

ClinPred

0.76

GERP RS

5.7

Varity_R

0.24

gMVP

0.64

Mutation Taster

=47/53

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over