Genetic Variant HSP90B1:p.Pro763Leu (chr12-103947336-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003299.3(HSP90B1):c.2288C>T(p.Pro763Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,296 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P763R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HSP90B1
NM_003299.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.10

Publications

0 publications found

Variant links:

Genes affected

HSP90B1 (HGNC:12028): (heat shock protein 90 beta family member 1) This gene encodes a member of a family of adenosine triphosphate(ATP)-metabolizing molecular chaperones with roles in stabilizing and folding other proteins. The encoded protein is localized to melanosomes and the endoplasmic reticulum. Expression of this protein is associated with a variety of pathogenic states, including tumor formation. There is a microRNA gene located within the 5' exon of this gene. There are pseudogenes for this gene on chromosomes 1 and 15. [provided by RefSeq, Aug 2012]

HSP90B1 links:

UQCC6 (HGNC:34450): (ubiquinol-cytochrome c reductase complex assembly factor 6) Involved in mitochondrial respiratory chain complex III assembly. Located in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

UQCC6 links:

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ACMG classification

Classification was made for transcript

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=0.40701294).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003299.3. 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
	HSP90B1	NM_003299.3	MANE Select	c.2288C>T	p.Pro763Leu	missense	Exon 17 of 18	NP_003290.1	P14625

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSP90B1	ENST00000299767.10	TSL:1 MANE Select	c.2288C>T	p.Pro763Leu	missense	Exon 17 of 18	ENSP00000299767.4	P14625
HSP90B1	ENST00000614327.2	TSL:1	c.2132C>T	p.Pro711Leu	missense	Exon 16 of 17	ENSP00000477660.2	A0A087WT78
HSP90B1	ENST00000681861.1		c.2288C>T	p.Pro763Leu	missense	Exon 17 of 17	ENSP00000506419.1	A0A7P0TAT8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32730

American (AMR)

AF:

0.00

AC:

AN:

43084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.00

AC:

AN:

85024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106080

Other (OTH)

AF:

0.00

AC:

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Benign

0.090

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.034

MetaRNN

Benign

0.41

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.67

PhyloP100

4.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.67

REVEL

Benign

0.22

Sift

Benign

0.078

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.48

MutPred

0.49

Loss of loop (P = 2e-04)

MVP

0.44

MPC

0.43

ClinPred

0.70

GERP RS

4.7

Varity_R

0.095

gMVP

0.19

Mutation Taster

=69/31

polymorphism

(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