chr6-44251054-T-G

Position:

• chr6-44251054-T-G

Variant summary

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

The NM_007355.4(HSP90AB1):​c.964T>G​(p.Ser322Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSP90AB1 NM_007355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSP90AB1	NM_007355.4	c.964T>G	p.Ser322Ala	missense_variant	7/12	ENST00000371646.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSP90AB1	ENST00000371646.10	c.964T>G	p.Ser322Ala	missense_variant	7/12	1	NM_007355.4	P1
HSP90AB1	ENST00000353801.7	c.964T>G	p.Ser322Ala	missense_variant	7/12	1		P1
HSP90AB1	ENST00000371554.2	c.964T>G	p.Ser322Ala	missense_variant	7/12	5		P1
HSP90AB1	ENST00000620073.4	c.964T>G	p.Ser322Ala	missense_variant	7/12	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Apr 27, 2023

The c.964T>G (p.S322A) alteration is located in exon 7 (coding exon 6) of the HSP90AB1 gene. This alteration results from a T to G substitution at nucleotide position 964, causing the serine (S) at amino acid position 322 to be replaced by an alanine (A). 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	0.19
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;.;.
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	.;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.017	.;D;D;D
Sift4G	Benign	0.062	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.73
MutPred		0.74		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.66
MPC		0.49
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.72
gMVP		0.25

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: chr6-44218791;