rs772570880

Positions:

• chr5-138566714-CCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_004134.7(HSPA9):​c.882_883del​(p.Val296Ter) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000146 in 1,612,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: HSPA9 NM_004134.7 frameshift, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.91

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 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-138566714-CCT-C is Pathogenic according to our data. Variant chr5-138566714-CCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224330.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA9	NM_004134.7	c.882_883del	p.Val296Ter	frameshift_variant, splice_region_variant	9/17	ENST00000297185.9	NP_004125.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA9	ENST00000297185.9	c.882_883del	p.Val296Ter	frameshift_variant, splice_region_variant	9/17	1	NM_004134.7	ENSP00000297185	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251418 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135888

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1460306 Hom.: 0 AF XY: 0.000161 AC XY: 117 AN XY: 726562

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Even-plus syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 12, 2017	- -

HSPA9-related disorder Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 25, 2023	PVS1, PM6_Strong, PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 19, 2023	The HSPA9 c.882_883delAG variant is predicted to result in premature protein termination (p.Val296*). This variant was reported in the compound heterozygous state in an individual with EVEN-plus syndrome (Royer-Bertrand et al. 2015. PubMed ID: 26598328) and apparently arose de novo in an individual with developmental delay (Supplementary Table 1, Deciphering Developmental Disorders Study. 2017. PubMed ID: 28135719). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137902403-CCT-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs772570880; hg19: chr5-137902403;