5-138556104-T-C

Variant summary

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

The NM_004134.7(HSPA9):c.1973A>G(p.Glu658Gly) variant causes a missense change. 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: HSPA9 NM_004134.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

HSPA9 (HGNC:5244): (heat shock protein family A (Hsp70) member 9) This gene encodes a member of the heat shock protein 70 gene family. The encoded protein is primarily localized to the mitochondria but is also found in the endoplasmic reticulum, plasma membrane and cytoplasmic vesicles. This protein is a heat-shock cognate protein. This protein plays a role in cell proliferation, stress response and maintenance of the mitochondria. A pseudogene of this gene is found on chromosome 2.[provided by RefSeq, May 2010]

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
HSPA9	NM_004134.7	c.1973A>G	p.Glu658Gly	missense_variant	17/17	ENST00000297185.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA9	ENST00000297185.9	c.1973A>G	p.Glu658Gly	missense_variant	17/17	1	NM_004134.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1973A>G (p.E658G) alteration is located in exon 17 (coding exon 17) of the HSPA9 gene. This alteration results from a A to G substitution at nucleotide position 1973, causing the glutamic acid (E) at amino acid position 658 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	0.30
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
Polyphen		0.95	P;P
Vest4		0.54
MutPred		0.15		Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);
MVP		0.42
MPC		0.30
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.45

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: chr5-137891793;