Variant 6-44249455-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007355.4(HSP90AB1):c.226A>C(p.Ile76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HSP90AB1
NM_007355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

Variant links:

Genes affected

HSP90AB1 (HGNC:5258): (heat shock protein 90 alpha family class B member 1) This gene encodes a member of the heat shock protein 90 family; these proteins are involved in signal transduction, protein folding and degradation and morphological evolution. This gene encodes the constitutive form of the cytosolic 90 kDa heat-shock protein and is thought to play a role in gastric apoptosis and inflammation. Alternative splicing results in multiple transcript variants. Pseudogenes have been identified on multiple chromosomes. [provided by RefSeq, Dec 2012]

HSP90AB1 links:

POLR1C (HGNC:):

POLR1C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31553552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90AB1	NM_007355.4 linkuse as main transcript	c.226A>C	p.Ile76Leu	missense_variant	3/12	ENST00000371646.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HSP90AB1	ENST00000371646.10 linkuse as main transcript	c.226A>C	p.Ile76Leu	missense_variant	3/12	1	NM_007355.4	P1
HSP90AB1	ENST00000353801.7 linkuse as main transcript	c.226A>C	p.Ile76Leu	missense_variant	3/12	1		P1
HSP90AB1	ENST00000371554.2 linkuse as main transcript	c.226A>C	p.Ile76Leu	missense_variant	3/12	5		P1
HSP90AB1	ENST00000620073.4 linkuse as main transcript	c.226A>C	p.Ile76Leu	missense_variant	3/12	5		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251470

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727188

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.226A>C (p.I76L) alteration is located in exon 3 (coding exon 2) of the HSP90AB1 gene. This alteration results from a A to C substitution at nucleotide position 226, causing the isoleucine (I) at amino acid position 76 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T;T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;.;.;.

M_CAP

Benign

0.042

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

3.0

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.2

.;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.030

.;D;D;D

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.20

B;B;B;B

Vest4

0.35

MutPred

0.43

Gain of catalytic residue at I76 (P = 0.0078);Gain of catalytic residue at I76 (P = 0.0078);Gain of catalytic residue at I76 (P = 0.0078);Gain of catalytic residue at I76 (P = 0.0078);

MVP

0.81

MPC

0.69

ClinPred

0.69

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over