5-138556481-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_004134.7(HSPA9):c.1933C>T(p.Leu645Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,612,568 control chromosomes in the GnomAD database, including 167,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.52 ( 22747 hom., cov: 32)

Exomes 𝑓: 0.43 ( 144917 hom. )

Consequence

HSPA9
NM_004134.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.926

Publications

38 publications found

Variant links:

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: AR, AD 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, Labcorp Genetics (formerly Invitae), Orphanet
autosomal recessive sideroblastic anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HSPA9 links:

ENSG00000299264 (HGNC:):

ENSG00000299264 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 5-138556481-G-A is Benign according to our data. Variant chr5-138556481-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1285357.

BP7

Synonymous conserved (PhyloP=0.926 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA9	NM_004134.7 link	c.1933C>T	p.Leu645Leu	synonymous_variant	Exon 16 of 17	ENST00000297185.9	NP_004125.3	P38646A0A384P5G6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA9	ENST00000297185.9 link	c.1933C>T	p.Leu645Leu	synonymous_variant	Exon 16 of 17	1	NM_004134.7	ENSP00000297185.3		P38646

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78862

AN:

151902

Hom.:

22700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.748

Gnomad AMI

AF:

0.544

Gnomad AMR

AF:

0.428

Gnomad ASJ

AF:

0.444

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.646

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.400

Gnomad OTH

AF:

0.498

GnomAD2 exomes

AF:

0.477

AC:

119856

AN:

251306

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.750

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.439

Gnomad EAS exome

AF:

0.783

Gnomad FIN exome

AF:

0.353

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.432

AC:

631084

AN:

1460548

Hom.:

144917

Cov.:

AF XY:

0.438

AC XY:

318512

AN XY:

726672

show subpopulations

African (AFR)

AF:

0.750

AC:

25114

AN:

33468

American (AMR)

AF:

0.392

AC:

17526

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

11565

AN:

26128

East Asian (EAS)

AF:

0.809

AC:

32121

AN:

39690

South Asian (SAS)

AF:

0.637

AC:

54938

AN:

86228

European-Finnish (FIN)

AF:

0.351

AC:

18662

AN:

53242

Middle Eastern (MID)

AF:

0.548

AC:

3145

AN:

5736

European-Non Finnish (NFE)

AF:

0.396

AC:

440282

AN:

1111014

Other (OTH)

AF:

0.459

AC:

27731

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

19476

38952

58427

77903

97379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14036

28072

42108

56144

70180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.519

AC:

78965

AN:

152020

Hom.:

22747

Cov.:

AF XY:

0.521

AC XY:

38717

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.749

AC:

31051

AN:

41484

American (AMR)

AF:

0.428

AC:

6532

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

1540

AN:

3466

East Asian (EAS)

AF:

0.803

AC:

4149

AN:

5170

South Asian (SAS)

AF:

0.646

AC:

3112

AN:

4818

European-Finnish (FIN)

AF:

0.350

AC:

3693

AN:

10552

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.400

AC:

27176

AN:

67946

Other (OTH)

AF:

0.500

AC:

1055

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1762

3524

5287

7049

8811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.440

Hom.:

27086

Bravo

AF:

0.533

Asia WGS

AF:

0.699

AC:

2433

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 25, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3, BA1, BP2, BP4 -

Even-plus syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.81

(source)

DANN

Benign

0.81

PhyloP100

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over