rs145860531

chr5-138558642-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_004134.7(HSPA9):c.1426G>A(p.Ala476Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,611,866 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: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: HSPA9 NM_004134.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.70

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26751482).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000329 (50/152038) while in subpopulation NFE AF= 0.000647 (44/68038). AF 95% confidence interval is 0.000494. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA9	NM_004134.7	c.1426G>A	p.Ala476Thr	missense_variant	12/17	ENST00000297185.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA9	ENST00000297185.9	c.1426G>A	p.Ala476Thr	missense_variant	12/17	1	NM_004134.7	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251370 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135866

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

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: 0.000739

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000363 AC: 530 AN: 1459828 Hom.: 0 Cov.: 29 AF XY: 0.000359 AC XY: 261 AN XY: 726334

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000453

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74244

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000562 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	- -

HSPA9-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2023

The HSPA9 c.1426G>A variant is predicted to result in the amino acid substitution p.Ala476Thr. This variant was reported in an individual with sporadic Parkinson disease (Burbulla et al. 2010. PubMed ID: 20817635). This variant is reported in 0.080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137894331-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
Polyphen		0.77	P;P
Vest4		0.71
MVP		0.51
MPC		0.30
ClinPred		0.083	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.56
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs145860531; hg19: chr5-137894331; COSMIC: COSV51866177; COSMIC: COSV51866177;