6-31810300-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005527.4(HSPA1L):c.1673A>C(p.Glu558Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0296 in 1,558,830 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.041 ( 187 hom., cov: 32)

Exomes 𝑓: 0.028 ( 740 hom. )

Consequence

HSPA1L
NM_005527.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 6.27

Publications

34 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021847188).

BP6

Variant 6-31810300-T-G is Benign according to our data. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-31810300-T-G is described in CliVar as Benign. Clinvar id is 372131.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1L	NM_005527.4 link	c.1673A>C	p.Glu558Ala	missense_variant	Exon 2 of 2	ENST00000375654.5	NP_005518.3	P34931A0A1U9X7W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1L	ENST00000375654.5 link	c.1673A>C	p.Glu558Ala	missense_variant	Exon 2 of 2	1	NM_005527.4	ENSP00000364805.4		P34931

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6315

AN:

152140

Hom.:

187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0830

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.0397

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0406

GnomAD2 exomes

AF:

0.0318

AC:

6531

AN:

205372

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.0847

Gnomad AMR exome

AF:

0.0326

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.00951

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0283

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0284

AC:

39887

AN:

1406572

Hom.:

740

Cov.:

AF XY:

0.0289

AC XY:

20117

AN XY:

695544

show subpopulations

African (AFR)

AF:

0.0858

AC:

2691

AN:

31380

American (AMR)

AF:

0.0318

AC:

1080

AN:

33966

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

254

AN:

22340

East Asian (EAS)

AF:

0.0140

AC:

550

AN:

39314

South Asian (SAS)

AF:

0.0436

AC:

3340

AN:

76518

European-Finnish (FIN)

AF:

0.0189

AC:

973

AN:

51424

Middle Eastern (MID)

AF:

0.0334

AC:

184

AN:

5516

European-Non Finnish (NFE)

AF:

0.0267

AC:

29004

AN:

1088070

Other (OTH)

AF:

0.0312

AC:

1811

AN:

58044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2091

4182

6272

8363

10454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1166

2332

3498

4664

5830

<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:

0.0415

AC:

6316

AN:

152258

Hom.:

187

Cov.:

AF XY:

0.0412

AC XY:

3070

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0829

AC:

3440

AN:

41518

American (AMR)

AF:

0.0304

AC:

465

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

AN:

3466

East Asian (EAS)

AF:

0.0137

AC:

AN:

5188

South Asian (SAS)

AF:

0.0400

AC:

193

AN:

4828

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10622

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0271

AC:

1842

AN:

68020

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

316

632

949

1265

1581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0310

Hom.:

421

Bravo

AF:

0.0436

TwinsUK

AF:

0.0280

AC:

104

ALSPAC

AF:

0.0291

AC:

112

ESP6500AA

AF:

0.0808

AC:

356

ESP6500EA

AF:

0.0264

AC:

227

ExAC

AF:

0.0330

AC:

4010

Asia WGS

AF:

0.0350

AC:

125

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28126021) -

HSPA1L-related disorder

Benign:1

Dec 23, 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). -

Inflammatory bowel disease 1

Other:1

Aug 06, 2016

Human Development and Health, University of Southampton

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

HSPA1L loss of function - Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

PhyloP100

6.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

REVEL

Benign

0.054

Sift

Uncertain

0.0080

Sift4G

Benign

0.21

Polyphen

0.30

Vest4

0.25

MPC

0.40

ClinPred

0.040

GERP RS

4.8

Varity_R

0.11

gMVP

0.31

Mutation Taster

=98/2

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