12-103932901-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003299.3(HSP90B1):c.370A>G(p.Asn124Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HSP90B1 NM_003299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

Genes affected

HSP90B1 (HGNC:12028): (heat shock protein 90 beta family member 1) This gene encodes a member of a family of adenosine triphosphate(ATP)-metabolizing molecular chaperones with roles in stabilizing and folding other proteins. The encoded protein is localized to melanosomes and the endoplasmic reticulum. Expression of this protein is associated with a variety of pathogenic states, including tumor formation. There is a microRNA gene located within the 5' exon of this gene. There are pseudogenes for this gene on chromosomes 1 and 15. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HSP90B1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1650356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90B1	NM_003299.3	c.370A>G	p.Asn124Asp	missense_variant	4/18	ENST00000299767.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSP90B1	ENST00000299767.10	c.370A>G	p.Asn124Asp	missense_variant	4/18	1	NM_003299.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450110 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722408

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: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 07, 2021

The c.370A>G (p.N124D) alteration is located in exon 4 (coding exon 4) of the HSP90B1 gene. This alteration results from a A to G substitution at nucleotide position 370, causing the asparagine (N) at amino acid position 124 to be replaced by an aspartic acid (D). 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	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.080	N;.;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.21	T;.;T;.
Sift4G	Benign	0.21	T;.;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.11, 0.12
MutPred		0.31		.;Gain of phosphorylation at S127 (P = 0.1156);Gain of phosphorylation at S127 (P = 0.1156);Gain of phosphorylation at S127 (P = 0.1156);
MVP		0.73
MPC		0.48
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: chr12-104326679;