Genetic Variant NM_005348.4:c.1-60A>C (chr14-102086438-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005348.4(HSP90AA1):c.1-60A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,579,192 control chromosomes in the GnomAD database, including 532,282 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 ( 40103 hom., cov: 33)

Exomes 𝑓: 0.83 ( 492179 hom. )

Consequence

HSP90AA1
NM_005348.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.738

Publications

17 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=-0.78).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSP90AA1	NM_005348.4	MANE Select	c.1-60A>C		intron	N/A	NP_005339.3
	HSP90AA1	NM_001017963.3		c.367-60A>C		intron	N/A	NP_001017963.2	P07900-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSP90AA1	ENST00000216281.13	TSL:1 MANE Select	c.1-60A>C	intron	N/A	ENSP00000216281.8	P07900-1
HSP90AA1	ENST00000334701.11	TSL:1	c.367-60A>C	intron	N/A	ENSP00000335153.7	P07900-2
HSP90AA1	ENST00000877286.1		c.-60A>C	5_prime_UTR	Exon 1 of 10	ENSP00000547345.1

Frequencies

GnomAD3 genomes

AF:

0.694

AC:

105461

AN:

152000

Hom.:

40097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.347

Gnomad AMI

AF:

0.931

Gnomad AMR

AF:

0.804

Gnomad ASJ

AF:

0.837

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.840

Gnomad FIN

AF:

0.779

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.838

Gnomad OTH

AF:

0.709

GnomAD4 exome

AF:

0.827

AC:

1179619

AN:

1427072

Hom.:

492179

AF XY:

0.829

AC XY:

590452

AN XY:

712468

show subpopulations

African (AFR)

AF:

0.326

AC:

10555

AN:

32330

American (AMR)

AF:

0.831

AC:

37123

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

21455

AN:

25896

East Asian (EAS)

AF:

0.779

AC:

30792

AN:

39512

South Asian (SAS)

AF:

0.846

AC:

72372

AN:

85570

European-Finnish (FIN)

AF:

0.796

AC:

42380

AN:

53274

Middle Eastern (MID)

AF:

0.798

AC:

4549

AN:

5698

European-Non Finnish (NFE)

AF:

0.844

AC:

912567

AN:

1080816

Other (OTH)

AF:

0.807

AC:

47826

AN:

59300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

10658

21315

31973

42630

53288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20228

40456

60684

80912

101140

<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:

105489

AN:

152120

Hom.:

40103

Cov.:

AF XY:

0.697

AC XY:

51854

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.347

AC:

14408

AN:

41506

American (AMR)

AF:

0.804

AC:

12297

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

2907

AN:

3472

East Asian (EAS)

AF:

0.791

AC:

4089

AN:

5168

South Asian (SAS)

AF:

0.839

AC:

4051

AN:

4828

European-Finnish (FIN)

AF:

0.779

AC:

8240

AN:

10584

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.838

AC:

56928

AN:

67950

Other (OTH)

AF:

0.711

AC:

1505

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1332

2665

3997

5330

6662

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:

0.768

Hom.:

91062

Bravo

AF:

0.679

Asia WGS

AF:

0.813

AC:

2828

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.46

(source)

DANN

Benign

0.40

PhyloP100

-0.74

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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