14-102082121-T-C

Position:

• chr14-102082121-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005348.4(HSP90AA1):​c.2079A>G​(p.Lys693Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,610,190 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (9 hom.)
• Consequence: HSP90AA1 NM_005348.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.180

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 14-102082121-T-C is Benign according to our data. Variant chr14-102082121-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 782308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.18 with no splicing effect.
• BS2: High AC in GnomAd4 at 394 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AA1	NM_005348.4	c.2079A>G	p.Lys693Lys	synonymous_variant	10/11	ENST00000216281.13	NP_005339.3
HSP90AA1	NM_001017963.3	c.2445A>G	p.Lys815Lys	synonymous_variant	11/12		NP_001017963.2
HSP90AA1	XM_011536718.3	c.2442A>G	p.Lys814Lys	synonymous_variant	11/12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AA1	ENST00000216281.13	c.2079A>G	p.Lys693Lys	synonymous_variant	10/11	1	NM_005348.4	ENSP00000216281.8
HSP90AA1	ENST00000334701.11	c.2445A>G	p.Lys815Lys	synonymous_variant	11/12	1		ENSP00000335153.7

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00298 AC: 746 AN: 250734 Hom.: 1 AF XY: 0.00281 AC XY: 381 AN XY: 135598

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00363 AC: 5292 AN: 1457868 Hom.: 9 Cov.: 31 AF XY: 0.00356 AC XY: 2584 AN XY: 725542

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00355

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74486

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00400 Hom.: 1

Bravo AF: 0.00292

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	HSP90AA1: BP4, BP7 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.7
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11547524; hg19: chr14-102548458;