Genetic Variant HSPA1L:p.Glu602Lys (chr6-31810169-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_005527.4(HSPA1L):c.1804G>A(p.Glu602Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,526,028 control chromosomes in the GnomAD database, including 78,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.26 ( 6366 hom., cov: 32)

Exomes 𝑓: 0.32 ( 72131 hom. )

Consequence

HSPA1L
NM_005527.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.91

Publications

136 publications found

Variant links:

Genes affected

HSPA1L (HGNC:5234): (heat shock protein family A (Hsp70) member 1 like) This gene encodes a 70kDa heat shock protein. In conjunction 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. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. [provided by RefSeq, Jul 2008]

HSPA1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037553012).

BP6

Variant 6-31810169-C-T is Benign according to our data. Variant chr6-31810169-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059263.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1L	NM_005527.4 link	c.1804G>A	p.Glu602Lys	missense_variant	Exon 2 of 2	ENST00000375654.5	NP_005518.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1L	ENST00000375654.5 link	c.1804G>A	p.Glu602Lys	missense_variant	Exon 2 of 2	1	NM_005527.4	ENSP00000364805.4

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38959

AN:

151994

Hom.:

6360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0582

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.381

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.277

GnomAD2 exomes

AF:

0.322

AC:

57626

AN:

179186

AF XY:

0.329

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.494

Gnomad EAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.346

Gnomad OTH exome

AF:

0.320

GnomAD4 exome

AF:

0.317

AC:

436075

AN:

1373916

Hom.:

72131

Cov.:

AF XY:

0.320

AC XY:

216215

AN XY:

675512

show subpopulations

African (AFR)

AF:

0.0446

AC:

1365

AN:

30596

American (AMR)

AF:

0.366

AC:

10594

AN:

28980

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

10052

AN:

20182

East Asian (EAS)

AF:

0.446

AC:

17306

AN:

38784

South Asian (SAS)

AF:

0.310

AC:

21465

AN:

69338

European-Finnish (FIN)

AF:

0.293

AC:

14668

AN:

50068

Middle Eastern (MID)

AF:

0.392

AC:

2106

AN:

5368

European-Non Finnish (NFE)

AF:

0.318

AC:

341351

AN:

1074032

Other (OTH)

AF:

0.303

AC:

17168

AN:

56568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15507

31015

46522

62030

77537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11248

22496

33744

44992

56240

<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:

0.256

AC:

38974

AN:

152112

Hom.:

6366

Cov.:

AF XY:

0.258

AC XY:

19212

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0581

AC:

2411

AN:

41518

American (AMR)

AF:

0.315

AC:

4821

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1777

AN:

3472

East Asian (EAS)

AF:

0.381

AC:

1971

AN:

5170

South Asian (SAS)

AF:

0.310

AC:

1493

AN:

4822

European-Finnish (FIN)

AF:

0.296

AC:

3128

AN:

10564

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.328

AC:

22300

AN:

67970

Other (OTH)

AF:

0.277

AC:

585

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1370

2741

4111

5482

6852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.317

Hom.:

30009

Bravo

AF:

0.250

ESP6500AA

AF:

0.0651

AC:

287

ESP6500EA

AF:

0.329

AC:

2826

ExAC

AF:

0.316

AC:

37728

Asia WGS

AF:

0.309

AC:

1079

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HSPA1L-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.3

PhyloP100

7.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.026

Polyphen

0.96

Vest4

0.26

MPC

0.91

ClinPred

0.027

GERP RS

5.9

Varity_R

0.26

gMVP

0.58

Mutation Taster

=90/10

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