12-103934187-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003299.3(HSP90B1):c.643C>T(p.His215Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: HSP90B1 NM_003299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HSP90B1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90B1	NM_003299.3	c.643C>T	p.His215Tyr	missense_variant	5/18	ENST00000299767.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSP90B1	ENST00000299767.10	c.643C>T	p.His215Tyr	missense_variant	5/18	1	NM_003299.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.643C>T (p.H215Y) alteration is located in exon 5 (coding exon 5) of the HSP90B1 gene. This alteration results from a C to T substitution at nucleotide position 643, causing the histidine (H) at amino acid position 215 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	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
Polyphen		1.0	.;D;.
Vest4		0.74, 0.73
MutPred		0.47		Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);
MVP		0.67
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.6
Varity_R		0.74
gMVP		0.70

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

Other links and lift over

dbSNP: rs1322917989; hg19: chr12-104327965;