Genetic Variant HSP90AA1:c.2090-66A>G (chr14-102081887-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001017963.3(HSP90AA1):c.2456-66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 846,106 control chromosomes in the GnomAD database, including 272,628 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 40021 hom., cov: 31)

Exomes 𝑓: 0.81 ( 232607 hom. )

Consequence

HSP90AA1
NM_001017963.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.286

Publications

15 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017963.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSP90AA1	NM_005348.4	MANE Select	c.2090-66A>G		intron	N/A	NP_005339.3
	HSP90AA1	NM_001017963.3		c.2456-66A>G		intron	N/A	NP_001017963.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HSP90AA1	ENST00000216281.13	TSL:1 MANE Select	c.2090-66A>G	intron	N/A	ENSP00000216281.8
HSP90AA1	ENST00000334701.11	TSL:1	c.2456-66A>G	intron	N/A	ENSP00000335153.7
HSP90AA1	ENST00000877282.1		c.2090-66A>G	intron	N/A	ENSP00000547341.1

Frequencies

GnomAD3 genomes

AF:

0.693

AC:

105319

AN:

151928

Hom.:

40015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.931

Gnomad AMR

AF:

0.804

Gnomad ASJ

AF:

0.837

Gnomad EAS

AF:

0.790

Gnomad SAS

AF:

0.839

Gnomad FIN

AF:

0.778

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.837

Gnomad OTH

AF:

0.708

GnomAD4 exome

AF:

0.814

AC:

564968

AN:

694060

Hom.:

232607

Cov.:

AF XY:

0.819

AC XY:

306256

AN XY:

373888

show subpopulations

African (AFR)

AF:

0.340

AC:

6452

AN:

18950

American (AMR)

AF:

0.831

AC:

36328

AN:

43696

Ashkenazi Jewish (ASJ)

AF:

0.827

AC:

17694

AN:

21406

East Asian (EAS)

AF:

0.777

AC:

28224

AN:

36302

South Asian (SAS)

AF:

0.845

AC:

59924

AN:

70896

European-Finnish (FIN)

AF:

0.794

AC:

41437

AN:

52202

Middle Eastern (MID)

AF:

0.795

AC:

3380

AN:

4254

European-Non Finnish (NFE)

AF:

0.836

AC:

343557

AN:

411182

Other (OTH)

AF:

0.795

AC:

27972

AN:

35172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6255

12510

18765

25020

31275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2906

5812

8718

11624

14530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.693

AC:

105347

AN:

152046

Hom.:

40021

Cov.:

AF XY:

0.697

AC XY:

51779

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.346

AC:

14330

AN:

41434

American (AMR)

AF:

0.805

AC:

12279

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

2904

AN:

3470

East Asian (EAS)

AF:

0.789

AC:

4078

AN:

5166

South Asian (SAS)

AF:

0.839

AC:

4042

AN:

4818

European-Finnish (FIN)

AF:

0.778

AC:

8227

AN:

10580

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.837

AC:

56922

AN:

67998

Other (OTH)

AF:

0.710

AC:

1501

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1297

2594

3892

5189

6486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.784

Hom.:

60826

Bravo

AF:

0.678

Asia WGS

AF:

0.814

AC:

2832

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

3.6

(source)

DANN

Benign

0.67

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over