3-52550462-G-T

Variant names:

• chr3-52550462-G-T
• rs142726131
• NM_001405607.1:c.4901C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001405607.1(PBRM1):​c.4901C>A​(p.Ala1634Glu) 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. A1634V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PBRM1 NM_001405607.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28534633).

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.4901C>A	p.Ala1634Glu	missense	Exon 31 of 32	NP_001392536.1
	PBRM1	NM_001405601.1		c.4901C>A	p.Ala1634Glu	missense	Exon 31 of 32	NP_001392530.1
	PBRM1	NM_001405598.1		c.4883C>A	p.Ala1628Glu	missense	Exon 30 of 31	NP_001392527.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBRM1	ENST00000707071.1	MANE Select	c.4901C>A	p.Ala1634Glu	missense	Exon 31 of 32	ENSP00000516722.1
	PBRM1	ENST00000296302.11	TSL:1	c.4856C>A	p.Ala1619Glu	missense	Exon 29 of 30	ENSP00000296302.7
	PBRM1	ENST00000409114.7	TSL:1	c.4745C>A	p.Ala1582Glu	missense	Exon 29 of 30	ENSP00000386643.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403926 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693872

African (AFR) AF: 0.00 AC: 0 AN: 31294

American (AMR) AF: 0.00 AC: 0 AN: 34270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39038

South Asian (SAS) AF: 0.00 AC: 0 AN: 77428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084034

Other (OTH) AF: 0.00 AC: 0 AN: 57816

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.000088	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.30		Gain of solvent accessibility (P = 0.005)
MVP		0.36
MPC		1.5
ClinPred		0.91	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.68
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: rs142726131; hg19: chr3-52584478;