Variant 14-102083224-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005348.4(HSP90AA1):c.1565T>C(p.Ile522Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

HSP90AA1
NM_005348.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08

Variant links:

Genes affected

HSP90AA1 (HGNC:5253): (heat shock protein 90 alpha family class A member 1) The protein encoded by this gene is an inducible molecular chaperone that functions as a homodimer. The encoded protein aids in the proper folding of specific target proteins by use of an ATPase activity that is modulated by co-chaperones. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

HSP90AA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052654058).

BS2

High AC in GnomAdExome4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AA1	NM_005348.4 linkuse as main transcript	c.1565T>C	p.Ile522Thr	missense_variant	9/11	ENST00000216281.13	NP_005339.3	P07900-1K9JA46
HSP90AA1	NM_001017963.3 linkuse as main transcript	c.1931T>C	p.Ile644Thr	missense_variant	10/12		NP_001017963.2	P07900-2Q86SX1
HSP90AA1	XM_011536718.3 linkuse as main transcript	c.1928T>C	p.Ile643Thr	missense_variant	10/12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSP90AA1	ENST00000216281.13 linkuse as main transcript	c.1565T>C	p.Ile522Thr	missense_variant	9/11	1	NM_005348.4	ENSP00000216281.8	P07900-1
HSP90AA1	ENST00000334701.11 linkuse as main transcript	c.1931T>C	p.Ile644Thr	missense_variant	10/12	1		ENSP00000335153.7	P07900-2
HSP90AA1	ENST00000554401.1 linkuse as main transcript	n.*994T>C		non_coding_transcript_exon_variant	7/7	1		ENSP00000451400.1	H0YJF5
HSP90AA1	ENST00000554401.1 linkuse as main transcript	n.*994T>C		3_prime_UTR_variant	7/7	1		ENSP00000451400.1	H0YJF5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251464

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135918

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:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727224

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:

0.000684

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

ExAC

AF:

0.000123

AC:

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, 2021

The c.1565T>C (p.I522T) alteration is located in exon 9 (coding exon 8) of the HSP90AA1 gene. This alteration results from a T to C substitution at nucleotide position 1565, causing the isoleucine (I) at amino acid position 522 to be replaced by a threonine (T). 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

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.094

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.7

N;.

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.23

N;N

REVEL

Uncertain

0.33

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.041

B;B

Vest4

0.52

MutPred

0.48

Gain of catalytic residue at M521 (P = 0.0065);.;

MVP

0.58

ClinPred

0.11

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.29

gMVP

0.38

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