5-138556543-C-T

Variant names:

• chr5-138556543-C-T
• rs1750524649
• NM_004134.7:c.1871G>A

Variant summary

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

The NM_004134.7(HSPA9):​c.1871G>A​(p.Arg624Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 4.86

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09058353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA9	NM_004134.7	c.1871G>A	p.Arg624Lys	missense_variant	Exon 16 of 17	ENST00000297185.9	NP_004125.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA9	ENST00000297185.9	c.1871G>A	p.Arg624Lys	missense_variant	Exon 16 of 17	1	NM_004134.7	ENSP00000297185.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1871G>A (p.R624K) alteration is located in exon 16 (coding exon 16) of the HSPA9 gene. This alteration results from a G to A substitution at nucleotide position 1871, causing the arginine (R) at amino acid position 624 to be replaced by a lysine (K). 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	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-1.1	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.54	.;N
REVEL	Benign	0.15
Sift	Benign	1.0	.;T
Sift4G	Benign	0.80	.;T
Polyphen		0.0	B;B
Vest4		0.36
MutPred		0.40		Gain of ubiquitination at R624 (P = 0.0048);Gain of ubiquitination at R624 (P = 0.0048);
MVP		0.27
MPC		0.27
ClinPred		0.67	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.28

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: rs1750524649; hg19: chr5-137892232; COSMIC: COSV51864881; COSMIC: COSV51864881;