6-44250379-A-G

Position:

• chr6-44250379-A-G

Variant summary

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

The NM_007355.4(HSP90AB1):​c.737A>G​(p.Glu246Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSP90AB1 NM_007355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

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]

POLR1C (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=0.18463993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90AB1	NM_007355.4	c.737A>G	p.Glu246Gly	missense_variant	6/12	ENST00000371646.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSP90AB1	ENST00000371646.10	c.737A>G	p.Glu246Gly	missense_variant	6/12	1	NM_007355.4	P1
HSP90AB1	ENST00000353801.7	c.737A>G	p.Glu246Gly	missense_variant	6/12	1		P1
HSP90AB1	ENST00000371554.2	c.737A>G	p.Glu246Gly	missense_variant	6/12	5		P1
HSP90AB1	ENST00000620073.4	c.737A>G	p.Glu246Gly	missense_variant	6/12	5		P1

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 04, 2024

The c.737A>G (p.E246G) alteration is located in exon 6 (coding exon 5) of the HSP90AB1 gene. This alteration results from a A to G substitution at nucleotide position 737, causing the glutamic acid (E) at amino acid position 246 to be replaced by a glycine (G). 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	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;T
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.031
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;.;.
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Uncertain	0.036	D;D;D;D
Polyphen		0.19	B;B;B;B
Vest4		0.33
MutPred		0.35		Gain of ubiquitination at K249 (P = 0.0747);Gain of ubiquitination at K249 (P = 0.0747);Gain of ubiquitination at K249 (P = 0.0747);Gain of ubiquitination at K249 (P = 0.0747);
MVP		0.49
MPC		0.69
ClinPred		0.73	D
GERP RS		3.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.12
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-44218116;