Variant chr6-44252053-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007355.4(HSP90AB1):c.1517G>A(p.Arg506Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HSP90AB1
NM_007355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

HSP90AB1 (HGNC:5258): (heat shock protein 90 alpha family class B member 1) This gene encodes a member of the heat shock protein 90 family; these proteins are involved in signal transduction, protein folding and degradation and morphological evolution. This gene encodes the constitutive form of the cytosolic 90 kDa heat-shock protein and is thought to play a role in gastric apoptosis and inflammation. Alternative splicing results in multiple transcript variants. Pseudogenes have been identified on multiple chromosomes. [provided by RefSeq, Dec 2012]

HSP90AB1 links:

POLR1C (HGNC:):

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90AB1	NM_007355.4 linkuse as main transcript	c.1517G>A	p.Arg506Gln	missense_variant	10/12	ENST00000371646.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HSP90AB1	ENST00000371646.10 linkuse as main transcript	c.1517G>A	p.Arg506Gln	missense_variant	10/12	1	NM_007355.4	P1
HSP90AB1	ENST00000353801.7 linkuse as main transcript	c.1517G>A	p.Arg506Gln	missense_variant	10/12	1		P1
HSP90AB1	ENST00000371554.2 linkuse as main transcript	c.1517G>A	p.Arg506Gln	missense_variant	10/12	5		P1
HSP90AB1	ENST00000620073.4 linkuse as main transcript	c.1517G>A	p.Arg506Gln	missense_variant	10/12	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251496

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135922

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:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

May 23, 2023

The c.1517G>A (p.R506Q) alteration is located in exon 10 (coding exon 9) of the HSP90AB1 gene. This alteration results from a G to A substitution at nucleotide position 1517, causing the arginine (R) at amino acid position 506 to be replaced by a glutamine (Q). 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

0.30

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;.;.

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

.;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0030

.;D;D;D

Sift4G

Uncertain

0.053

T;T;T;T

Polyphen

0.59

P;P;P;P

Vest4

0.81

MutPred

0.49

Loss of MoRF binding (P = 0.0318);Loss of MoRF binding (P = 0.0318);Loss of MoRF binding (P = 0.0318);Loss of MoRF binding (P = 0.0318);

MVP

0.73

MPC

1.3

ClinPred

0.64

GERP RS

4.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.84

gMVP

0.46

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