chr14-102083857-G-C

Position:

• chr14-102083857-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005348.4(HSP90AA1):​c.1274C>G​(p.Thr425Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSP90AA1 NM_005348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23620188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AA1	NM_005348.4	c.1274C>G	p.Thr425Ser	missense_variant	7/11	ENST00000216281.13	NP_005339.3
HSP90AA1	NM_001017963.3	c.1640C>G	p.Thr547Ser	missense_variant	8/12		NP_001017963.2
HSP90AA1	XM_011536718.3	c.1637C>G	p.Thr546Ser	missense_variant	8/12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AA1	ENST00000216281.13	c.1274C>G	p.Thr425Ser	missense_variant	7/11	1	NM_005348.4	ENSP00000216281.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Sep 03, 2024

The c.1274C>G (p.T425S) alteration is located in exon 7 (coding exon 6) of the HSP90AA1 gene. This alteration results from a C to G substitution at nucleotide position 1274, causing the threonine (T) at amino acid position 425 to be replaced by a serine (S). 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	0.066
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Benign	0.084	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.089
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.60	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.32	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.39	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.025	B;B
Vest4		0.38
MutPred		0.38		Gain of catalytic residue at L421 (P = 6e-04);.;
MVP		0.54
ClinPred		0.73	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.35
gMVP		0.13

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: chr14-102550194;