Genetic Variant HSP90B1:p.Leu627Phe (chr12-103943308-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003299.3(HSP90B1):c.1879C>T(p.Leu627Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HSP90B1
NM_003299.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSP90B1	NM_003299.3 link	c.1879C>T	p.Leu627Phe	missense_variant	Exon 13 of 18	ENST00000299767.10	NP_003290.1	P14625V9HWP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSP90B1	ENST00000299767.10 link	c.1879C>T	p.Leu627Phe	missense_variant	Exon 13 of 18	1	NM_003299.3	ENSP00000299767.4		P14625

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250658

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1879C>T (p.L627F) alteration is located in exon 13 (coding exon 13) of the HSP90B1 gene. This alteration results from a C to T substitution at nucleotide position 1879, causing the leucine (L) at amino acid position 627 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.076

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.54

Sift

Benign

0.055

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.70

MutPred

0.79

Gain of methylation at K628 (P = 0.038);

MVP

0.69

MPC

0.94

ClinPred

0.97

GERP RS

5.8

Varity_R

0.41

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over