14-102085359-C-T

Variant names:

• chr14-102085359-C-T
• rs764012202
• NM_005348.4:c.602G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005348.4(HSP90AA1):​c.602G>A​(p.Arg201Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HSP90AA1 NM_005348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27777886).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSP90AA1	NM_005348.4	c.602G>A	p.Arg201Gln	missense_variant	Exon 4 of 11	ENST00000216281.13	NP_005339.3
HSP90AA1	NM_001017963.3	c.968G>A	p.Arg323Gln	missense_variant	Exon 5 of 12		NP_001017963.2
HSP90AA1	XM_011536718.3	c.965G>A	p.Arg322Gln	missense_variant	Exon 5 of 12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSP90AA1	ENST00000216281.13	c.602G>A	p.Arg201Gln	missense_variant	Exon 4 of 11	1	NM_005348.4	ENSP00000216281.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251320 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460488 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602G>A (p.R201Q) alteration is located in exon 4 (coding exon 3) of the HSP90AA1 gene. This alteration results from a G to A substitution at nucleotide position 602, causing the arginine (R) at amino acid position 201 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	0.31
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.054	T;D;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.010	B;P;.
Vest4		0.54
MutPred		0.60		Loss of MoRF binding (P = 0.0578);.;.;
MVP		0.61
ClinPred		0.93	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.30

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: rs764012202; hg19: chr14-102551696;