Genetic Variant HSPA1A:p.Val570Val (chr6-31817466-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_005345.6(HSPA1A):c.1710G>T(p.Val570Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 28 hom., cov: 31)

Exomes 𝑓: 0.0036 ( 280 hom. )

Failed GnomAD Quality Control

Consequence

HSPA1A
NM_005345.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.589

Publications

3 publications found

Variant links:

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

HSPA1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP7

Synonymous conserved (PhyloP=-0.589 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6 link	c.1710G>T	p.Val570Val	synonymous_variant	Exon 1 of 1	ENST00000375651.7	NP_005336.3	P0DMV8-1P0DMV9A8K5I0B3KTT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7 link	c.1710G>T	p.Val570Val	synonymous_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5		P0DMV8-1
HSPA1A	ENST00000608703.2 link	c.1215G>T	p.Val405Val	synonymous_variant	Exon 2 of 2	2		ENSP00000477378.1		V9GZ37

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1894

AN:

151486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00841

Gnomad OTH

AF:

0.0189

GnomAD2 exomes

AF:

0.00132

AC:

322

AN:

243216

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.000881

Gnomad ASJ exome

AF:

0.00493

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000685

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00356

AC:

5147

AN:

1446544

Hom.:

280

Cov.:

AF XY:

0.00367

AC XY:

2636

AN XY:

719022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00496

AC:

163

AN:

32872

American (AMR)

AF:

0.00400

AC:

177

AN:

44234

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

799

AN:

24920

East Asian (EAS)

AF:

0.0355

AC:

1391

AN:

39188

South Asian (SAS)

AF:

0.00280

AC:

234

AN:

83522

European-Finnish (FIN)

AF:

0.00126

AC:

AN:

52210

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.00168

AC:

1859

AN:

1104460

Other (OTH)

AF:

0.00624

AC:

372

AN:

59616

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.293

Heterozygous variant carriers

398

795

1193

1590

1988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0125

AC:

1898

AN:

151604

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

928

AN XY:

74074

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0158

AC:

652

AN:

41328

American (AMR)

AF:

0.0154

AC:

234

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.0616

AC:

208

AN:

3374

East Asian (EAS)

AF:

0.0142

AC:

AN:

5154

South Asian (SAS)

AF:

0.0203

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00841

AC:

571

AN:

67870

Other (OTH)

AF:

0.0187

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.332

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00463

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.4

(source)

DANN

Benign

0.94

PhyloP100

-0.59

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

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

Computational scores

Splicing

Publications

Other links and lift over