chr14-102083276-A-C

Position:

• chr14-102083276-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005348.4(HSP90AA1):​c.1513T>G​(p.Ser505Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSP90AA1 NM_005348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AA1	NM_005348.4	c.1513T>G	p.Ser505Ala	missense_variant	9/11	ENST00000216281.13	NP_005339.3
HSP90AA1	NM_001017963.3	c.1879T>G	p.Ser627Ala	missense_variant	10/12		NP_001017963.2
HSP90AA1	XM_011536718.3	c.1876T>G	p.Ser626Ala	missense_variant	10/12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AA1	ENST00000216281.13	c.1513T>G	p.Ser505Ala	missense_variant	9/11	1	NM_005348.4	ENSP00000216281.8
HSP90AA1	ENST00000334701.11	c.1879T>G	p.Ser627Ala	missense_variant	10/12	1		ENSP00000335153.7
HSP90AA1	ENST00000554401.1	n.*942T>G		non_coding_transcript_exon_variant	7/7	1		ENSP00000451400.1
HSP90AA1	ENST00000554401.1	n.*942T>G		3_prime_UTR_variant	7/7	1		ENSP00000451400.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1513T>G (p.S505A) alteration is located in exon 9 (coding exon 8) of the HSP90AA1 gene. This alteration results from a T to G substitution at nucleotide position 1513, causing the serine (S) at amino acid position 505 to be replaced by an alanine (A). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.079	T;T
Polyphen		0.70	P;P
Vest4		0.70
MutPred		0.71		Gain of catalytic residue at Q501 (P = 0.0017);.;
MVP		0.73
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-102549613;