rs2049187841

Variant names:

• chr14-102084920-C-G
• NM_005348.4:c.742G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-102084920-C-G
• chr14-102084920-C-T

Variant summary

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

The NM_005348.4(HSP90AA1):​c.742G>C​(p.Glu248Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E248K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HSP90AA1 NM_005348.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2035017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSP90AA1	NM_005348.4	c.742G>C	p.Glu248Gln	missense_variant	Exon 5 of 11	ENST00000216281.13	NP_005339.3
HSP90AA1	NM_001017963.3	c.1108G>C	p.Glu370Gln	missense_variant	Exon 6 of 12		NP_001017963.2
HSP90AA1	XM_011536718.3	c.1105G>C	p.Glu369Gln	missense_variant	Exon 6 of 12		XP_011535020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSP90AA1	ENST00000216281.13	c.742G>C	p.Glu248Gln	missense_variant	Exon 5 of 11	1	NM_005348.4	ENSP00000216281.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428080 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 712156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.060
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.085	B;P
Vest4		0.41
MutPred		0.37		Gain of ubiquitination at K245 (P = 0.1204);.;
MVP		0.82
ClinPred		0.82	D
GERP RS		3.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Varity_R		0.11
gMVP		0.46

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: chr14-102551257; COSMIC: COSV53487968; COSMIC: COSV53487968;