Variant 12-103942596-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003299.3(HSP90B1):c.1444G>T(p.Asp482Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HSP90B1
NM_003299.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.83

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90B1	NM_003299.3 linkuse as main transcript	c.1444G>T	p.Asp482Tyr	missense_variant	12/18	ENST00000299767.10	NP_003290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90B1	ENST00000299767.10 linkuse as main transcript	c.1444G>T	p.Asp482Tyr	missense_variant	12/18	1	NM_003299.3	ENSP00000299767	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251182

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

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:

0.00000274

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.1444G>T (p.D482Y) alteration is located in exon 12 (coding exon 12) of the HSP90B1 gene. This alteration results from a G to T substitution at nucleotide position 1444, causing the aspartic acid (D) at amino acid position 482 to be replaced by a tyrosine (Y). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.0070

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.25

Sift

Benign

0.18

Sift4G

Benign

0.068

Polyphen

0.98

Vest4

0.66

MutPred

0.52

Gain of loop (P = 0.0502);

MVP

0.49

MPC

1.2

ClinPred

0.92

GERP RS

5.0

Varity_R

0.50

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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