5-138557878-C-T

Variant names:

• chr5-138557878-C-T
• rs1463769778
• NM_004134.7:c.1624G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004134.7(HSPA9):​c.1624G>A​(p.Glu542Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA9 NM_004134.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• Publications: 1 publications found

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]

HSPA9 Gene-Disease associations (from GenCC):

• autosomal dominant sideroblastic anemia

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• even-plus syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal recessive sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000299264 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004134.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA9	NM_004134.7	MANE Select	c.1624G>A	p.Glu542Lys	missense	Exon 13 of 17	NP_004125.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA9	ENST00000297185.9	TSL:1 MANE Select	c.1624G>A	p.Glu542Lys	missense	Exon 13 of 17	ENSP00000297185.3	P38646
	HSPA9	ENST00000946847.1		c.1807G>A	p.Glu603Lys	missense	Exon 14 of 18	ENSP00000616906.1
	HSPA9	ENST00000936338.1		c.1642G>A	p.Glu548Lys	missense	Exon 13 of 17	ENSP00000606397.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450420 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722270

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103358

Other (OTH) AF: 0.00 AC: 0 AN: 59928

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.41
Sift	Benign	0.031	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.56		Gain of MoRF binding (P = 0.0039)
MVP		0.52
MPC		0.98
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.49
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1463769778; hg19: chr5-137893567;