3-52648421-G-C

Variant names:

• chr3-52648421-G-C
• rs587778593
• NM_001405607.1:c.736C>G

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.736C>G​(p.His246Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. H246N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PBRM1 NM_001405607.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• 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]

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=0.20214728).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBRM1	NM_001405607.1	MANE Select	c.736C>G	p.His246Asp	missense	Exon 8 of 32	NP_001392536.1
	PBRM1	NM_001405608.1		c.-214C>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 27	NP_001392537.1
	PBRM1	NM_001405625.1		c.-755C>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 30	NP_001392554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBRM1	ENST00000707071.1	MANE Select	c.736C>G	p.His246Asp	missense	Exon 8 of 32	ENSP00000516722.1
	PBRM1	ENST00000296302.11	TSL:1	c.736C>G	p.His246Asp	missense	Exon 7 of 30	ENSP00000296302.7
	PBRM1	ENST00000409114.7	TSL:1	c.736C>G	p.His246Asp	missense	Exon 7 of 30	ENSP00000386643.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		4.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.16
Sift	Benign	0.77	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	B
Vest4		0.48
MutPred		0.46		Loss of catalytic residue at M248 (P = 0.0582)
MVP		0.64
MPC		1.2
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.66
Mutation Taster		=60/40	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: rs587778593; hg19: chr3-52682437;